(Download PDF) The MD Anderson Manual of Medical Oncology 4Th Edition Hagop Kantarjian Full Chapter PDF

The MD Anderson Manual of Medical
Oncology 4th Edition Hagop Kantarjian

Visit to download the full and correct content document:
https://ebookmass.com/product/the-md-anderson-manual-of-medical-oncology-4th-ed
ition-hagop-kantarjian/
More products digital (pdf, epub, mobi) instant
download maybe you interests ...
The MD Anderson Manual of Medical Oncology 3rd Edition

Hagop M. Kantarjian
https://ebookmass.com/product/the-md-anderson-manual-of-medical-
oncology-3rd-edition-hagop-m-kantarjian/
Sectional Anatomy by MRI and CT 4th Edition Mark W.

Anderson Md
https://ebookmass.com/product/sectional-anatomy-by-mri-and-
ct-4th-edition-mark-w-anderson-md/
Diagnostic Pathology: Molecular Oncology 2nd Edition

Mohammad A Vasef Md
https://ebookmass.com/product/diagnostic-pathology-molecular-
oncology-2nd-edition-mohammad-a-vasef-md/
Psycho-Oncology 4th Edition William Breitbart (Editor)
https://ebookmass.com/product/psycho-oncology-4th-edition-
william-breitbart-editor/
Pediatric Transplant and Oncology Infectious Diseases
1st Edition William J. Steinbach Md
https://ebookmass.com/product/pediatric-transplant-and-oncology-
infectious-diseases-1st-edition-william-j-steinbach-md/
Principles of medical biochemistry 4th edition Edition

Meisenberg
https://ebookmass.com/product/principles-of-medical-
biochemistry-4th-edition-edition-meisenberg/
DiSaia and Creasman Clinical Gynecologic Oncology 10th

Edition William T. Creasman Md (Editor)
https://ebookmass.com/product/disaia-and-creasman-clinical-
gynecologic-oncology-10th-edition-william-t-creasman-md-editor/
(eBook PDF) Essentials of Medical Language 4th Edition
https://ebookmass.com/product/ebook-pdf-essentials-of-medical-
language-4th-edition/
Escourolle and Poirier's Manual of Basic Neuropathology

6th Edition Francoise Gray Md (Editor)
https://ebookmass.com/product/escourolle-and-poiriers-manual-of-
basic-neuropathology-6th-edition-francoise-gray-md-editor/
The MD Anderson Manual
of Medical Oncology
Notice
Medicine is an ever-changing science. As new research and clinical experi-
ence broaden our knowledge, changes in treatment and drug therapy are
required. The authors and the publisher o this work have checked with
sources believed to be reliable in their eorts to provide inormation that is
complete and generally in accord with the standards accepted at the time o
publication. However, in view o the possibility o human error or changes
in medical sciences, neither the authors nor the publisher nor any other
party who has been involved in the preparation or publication o this work
warrants that the inormation contained herein is in every respect accurate
or complete, and they disclaim all responsibility or any errors or omissions
or or the results obtained rom use o the inormation contained in this
work. Readers are encouraged to conirm the inormation contained herein
with other sources. For example and in particular, readers are advised to
check the product inormation sheet included in the package o each drug
they plan to administer to be certain that the inormation contained in this
work is accurate and that changes have not been made in the recommended
dose or in the contraindications or administration. This recommendation is
o particular importance in connection with new or inrequently used drugs.
The MD Anderson
Manual of
Medical Oncology
Fourth Edition
Editors
Hagop M. Katarjia, MD
Proessor o Medicine
Chair, Department o Leukemia
The University o Texas MD Anderson Cancer Center
Houston, Texas
Robrt A. Wolff, MD
Department o Gastrointestinal Medical Oncology
Houston, Texas
Alyssa G. Ribr, MD
Department o General Oncology
Houston, Texas
New York Chicago San Francisco Athens London Madrid Mexico City
Milan New Delhi Singapore Sydney Toronto
Copyright © 2022 by McGraw Hill, LLC. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no
part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without
the prior written permission of the publisher.
ISBN: 978-1-26-046765-9
MHID: 1-26-046765-1
The material in this eBook also appears in the print version of this title: ISBN: 978-1-26-046764-2,
MHID: 1-26-046764-3.
eBook conversion by codeMantra

Version 1.0
All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked
name, we use names in an editorial fashion only, and to the benet of the trademark owner, with no intention of infringement of the
trademark. Where such designations appear in this book, they have been printed with initial caps.
McGraw-Hill Education eBooks are available at special quantity discounts to use as premiums and sales promotions or for use in corpo-
rate training programs. To contact a representative, please visit the Contact Us page at www.mhprofessional.com.
TERMS OF USE
This is a copyrighted work and McGraw-Hill Education and its licensors reserve all rights in and to the work. Use of this work is subject
to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may
not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate,
sell, publish or sublicense the work or any part of it without McGraw-Hill Education’s prior consent. You may use the work for your
own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if
you fail to comply with these terms.
THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION AND ITS LICENSORS MAKE NO GUARANTEES OR WAR-
RANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING
THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR
OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED
TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill Education
and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its opera-
tion will be uninterrupted or error free. Neither McGraw-Hill Education nor its licensors shall be liable to you or anyone else for any
inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill Education has no
responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill Education and/
or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or
inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply
to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.
Dedication
Emil J Freireich, MD
March 16,1927 – February 1, 2021
Dedication of the fourth Edition of “The MD Anderson Manual of Medical Oncology” to Emil J
Freireich, a Legendary Trailblazer in Cancer and Leukemia Research and Therapy
Emil J Freireich was a ounding ather o modern cancer research, and leader o the world’s rst generation o
cancer research pioneers.
Following his medical training at the University o Illinois College o Medicine at Chicago, and internal medi-
cine training at Cook County Hospital and Presbyterian Hospital, he moved to the National Cancer Institute
(1955-1965), where he made his rst seminal discoveries: the benet o platelet transusions in reducing bleeding;
the design o the rst-ever continuous-fow blood cell separator that extracted platelets rom whole blood; the
development o multidrug regimens that paved the way or the cure o childhood acute lymphoblastic leukemia
(ALL).
In 1965, Freireich moved to Houston and spent the next 55 years at MD Anderson, his real home. He was a
ounding member o the institution, which owed much o its early success and reputation to his work and that
o his mentees. Freireich’s name became synonymous with that o MD Anderson. He created a department o
Developmental Therapeutics (DT), dedicated to medical cancer research and to developing novel cancer strate-
gies. Over the next 15 years, he attracted hundreds o cancer researchers rom all over the world who, like him,
were convinced that cancer was curable and were determined to accomplish this. Many o the early chemo-
therapy drugs (cytarabine, Adriamycin, cisplatin, others) were developed during this period, and became building
blocks or curative combinations. Together with Dr Gerald Bodey, Freireich discovered the association between
neutropenia and increased risk o inections and developed the concept o empiric antibiotic therapy to prevent
and treat ever and inections in patients with cancer. This, along with platelet transusions, made cancer care
saer and opened the research venues or intensive chemotherapy and stem cell transplantation in hematologic
and solid tumors. The pheresis machines he helped to create were later used to collect stem cells or the purpose
o transplantation.
In DT, and later as a senior leader at MD Anderson, Freireich trained and mentored hundreds o oncologists, many
o whom later created their own legacies and helped hundreds o thousands o patients with cancer. He also cre-
ated in 1966 the rst training ellowship program in cancer and established clinical-translational research and care
as a new critical discipline in oncology.
To the hundreds o us who trained under Freireich, he and his stories and education are indelibly cemented in our
memories. In recognition o his massive contributions to education in cancer research and care, we dedicate this
ourth edition to Emil J Freireich.
v
This page intentionally left blank
Contents
Contributors xi 9. aggrssv B-Cll Lyphos 191

A Brie History o MD Anderson Cancer Center xxv Raphael Steiner, Jason R. Westin, Sergej N. Konoplev, Luis
E. Fayad, L. Jefrey Medeiros
Foreword xxix
10. mntl Cll Lypho 227
Preace xxxi Preetesh Jain, Michael Wang
11. Nodl Prphrl T-Cll Lypho 253
I Leukemia Ranjit Nair, Francisco Vega, Swaminathan P. Iyer
Section Editor: William G. Wierda 12. Ctnos Lyphos 269
1. act Lyphoblstc L 3 Auris Huen
Hind Raei, Sergej N. Konoplev, Sa A. Wang, 13. Hodgn Lypho 291
Nicholas J. Short, Hagop M. Kantarjian, Elias J. Jabbour Collin K. Chin, L. Jefrey Medeiros, Fredrick B.
2. adlt act mylod L 23 Hagemeister, Hun J. Lee
apan M. Kadia, Joseph D. Khoury, Farhad Ravandi 14. Systc inoglobln Lght Chn
aylodoss 323
3. Chronc Lyphocytc L
nd assoctd Dsordrs 49 Gregory P. Kauman, Muzafar H. Qazilbash, Krina Patel,
Sheeba Tomas, Robert Z. Orlowski, Hans C. Lee
Nitin Jain, Philip Tompson, Carlos Bueso-Ramos,
Susan M. O’Brien, William G. Wierda 15. Wldnströ mcroglobln 333
4. Chronc mylod L 67 Melody Becnel, Gregory P. Kauman,
Elisabet E. Manasanch, Krina Patel, Hans C. Lee,
Koji Sasaki, Elias Jabbour, Jorge Cortes, Robert Z. Orlowski, Sheeba Tomas
Hagop Kantarjian
16. mltpl mylo 341
5. mylodysplstc Syndros: Th mD andrson
Paul Lin, Gregory P. Kauman, Hans C. Lee,
Cncr Cntr approch 91
Elisabet E. Manasanch, Melody Becnel, Sheeba Tomas,
Kelly Chien, Carlos Bueso-Ramos, Donna Weber, Robert Z. Orlowski, Krina Patel
Guillermo Garcia-Manero
17. Clllr Thrpy for Lypho 363
6. Phldlph Chrooso-Ngtv
Sairah Ahmed, Simrit Parmar, Sattva Neelapu
myloprolfrtv Noplss 119
Prithviraj Bose, Lucia Masarova, Hesham M. Amin,
Srdan Verstovsek III STem CeLL TRaNSPLaNTaTiON
Section Editor: Elizabeth J. Shpall
II LYmPHOma aND mYeLOma 18. atologos Htopotc Progntor-Cll
Section Editor: Nathan H. Fowler Trnsplntton 383
Neeraj Saini, Yago Nieto
7. Follclr Lypho 165
Paolo Strati, Jillian R Gunther, L. Jefrey Medeiros, Loretta 19. allognc Trnsplntton 397
J. Nastoupil Rohtesh S. Mehta, Chitra Hosing
8. mrgnl Zon nd Othr Sll Cll 20. altrntv Donor Trnsplnts: Cord Blood
Lyphos 183 Trnsplnt 427
Melody Becnel, Felipe Samaniego Hind Raei, Amanda Olson, Rohtesh S. Mehta, Betul Oran,
Katayoun Rezvani, Elizabeth J. Shpall
vii
v Cotts
21. altrntv Donor Trnsplnts: 31. Sll Bowl Cncr nd appndcl
Hplodntcl Htopotc Tors 707
St Cll Trnsplntton 447 Pat Gulhati, John Paul Shen, Kanwal P. Raghav,
Samer A. Srour, Richard E. Champlin, Michael J. Overman
Stean O. Ciurea
32. Colorctl Cncr 733
22. Clllr Thrpy n allognc Htopotc Arvind Dasari, Benny Johnson, Christine Parseghian,
Cll Trnsplntton 457 Kanwal P. Raghav, Scott Kopetz
Amanda Olson, Jeremy Ramdial, Uri Greenbaum, Paul
33. anl Cncr 765
Lin, Katayoun Rezvani, Partow Kebriaei
Emma Holliday, Van Morris, Craig A. Messick
34. Nrondocrn Tors 781
iV LuNG CaNCeR Jessica E. Maxwell, James C. Yao, Daniel M. Halperin
Section Editor: Bonnie S. Glisson
23. Sll Cll Crcno o th Lng 475 Vii BReaST CaNCeR
Jeremy A. Ross, Lauren A. Byers, Carl M. Gay Section Editor: Gabriel N. Hortobagyi
24. Non–Sll Cll Lng Cncr: Gnrl
Prncpls, mngnt o Loclzd Dss, 35. erly-Stg nd Loclly advncd Brst
nd Trtnt o mtsttc Dss wthot Cncr 803
Oncogn Drvrs 495 Demetria Smith-Graziani, Mariana Chavez-MacGregor
Mehmet Altan, Joshua M Gulvin, George Simon, 36. mtsttc Brst Cncr 829
Bonnie Glisson Haven R. Garber, Meghan S. Karuturi,
25. Trgtd Thrps n Non–Sll Cll Lng Gabriel N. Hortobagyi
Cncr 535 37. mngnt o Loclly advncd Brst
Yasir Y. Elamin, Don L. Gibbons, Marcelo V. Negrao Cncr, incldng intory Brst
Cncr 863
Bora Lim, Gabriel N. Hortobagyi
V HeAD AnD neCK CAnCeR
Section Editor: Bonnie S. Glisson 38. Spcl Sttons n Brst Cncr 875
Rachel M. Layman
26. Hd nd Nck Cncr 555
Ruth Sacks, David Boyce-Fappiano, Amy Moreno,
Frank Mott Viii GYNeCOLOGiC maLiGNaNCieS
Section Editor: Karen H. Lu
Vi GaSTROiNTeSTiNaL 39. Ovrn Cncr 897

CaNCeR Roni Nitecki, Lauren P. Cobb, Amir A. Jazaeri,
J. Alejandro Rauh-Hain
Section Editor: Robert A. Wol
40. Tors o th utrn Corps 931
27. Gstrc, Gstrosophgl Jncton, nd Michaela A. Onstad, Shannon N. Westin, Karen H. Lu
esophgl Cncrs 579
Mariela Blum Murphy, Elena Elimova, 41. Tors o th utrn Crvx 955
Ahmed Abdelhakeem, Jaer Ajani Gloria Salvo, Mila P. Salcedo, Sol Basabe, Pedro . Ramirez
28. Pncrtc Cncr 619 42. Gsttonl Trophoblstc Dss 983
Jonathan D. Mizrahi, Anirban Maitra, Han . Cun, Aaron Shaer
Robert A. Wol
29. Blry Trct Cncr 647 ix GeNiTOuRiNaRY

Shalini Makawita, Sunyoung Lee, Yun Shin Chun, maLiGNaNCieS
Millicent A. Roach, Eugene J. Koay, Milind Javle
Section Editor: Nizar M. annir
30. Hptoclllr Crcno 677
Sunyoung S. Lee, Hao Chi Zhang, Hop S. ran Cao, 43. Rnl Cll Crcno 1005
Sudha Kodali, Joshua D. Kuban, Eugene J. Koay, Andrew W. Hahn, Jose A. Karam, Christopher G. Wood,
Rony Avritscher, Ahmed O. Kaseb Nizar M. annir
Cotts 
44. Blddr Cncr 1027 55. Cncr Gnocs 1283

Alexander Y. Andreev-Drakhlin, Ashish M. Kamat, Jason A. Willis, Jennier B. Goldstein, Zhijing Zhang,
Arlene O. Sieer-Radtke Andy Futreal
45. Prostt Cncr 1049 56. ino-oncology 1297

Patrick Pilié, Paul Viscuse, Christopher J. Logothetis, Bilal A. Siddiqui, Sangeeta Goswami, James P. Allison,
Paul G. Corn Padmanee Sharma
46. Pnl Cncr 1071 57. Trgtd Thrpy n Cncr 1323

Jad Chahoud, Curtis A. Pettaway Rabih Said, Apostolia-Maria simberidou
47. Gr Cll Tors 1081 58. Vrl inctons n Ptnts
Joseph A. Moore, Shi-Ming u wth Cncr 1345
Fareed Khawaja, Roy F. Chemaly
NeuROLOGiC TumORS 59. Fngl inctons n Ptnts wth

x Cncr 1363
Section Editor: John de Groot
Bruno P. Granwehr, Dimitrios P. Kontoyiannis
48. Tors o th Cntrl Nrvos 60. endocrn nd mtbolc Coplctons
Syst 1105 o Cncr Thrpy 1381
Shiao-Pei Weathers, Barbara O’Brien, Ashley Aaroe, Rachael Hosein, Sara Bedrose, Rebecca Jeun,
Debra Yeboa, Sujit Prabhu, John de Groot Jeena M. Varghese, Sonali N. Tosani
61. Oncologc ergncs 1407

xi maLiGNaNT meLaNOma Sai-Ching Jim Yeung, Ellen F. Manzullo,
Section Editor: Michael A. Davies Patrick Chafari
62. Oncocrdology 1435

49. mlno 1133
Elie Mouhayar, Danielle El-Haddad,
Houssein Saa, Jane Mattei, Andrew J. Bishop, Peter Kim, Kara Tompson, Cezar Iliescu,
Emily Z. Keung, Sirisha Yadugiri, Michael A. Davies, Abdulrazzak Zaria
Isabella C. Glitza Oliva
63. Plonry Coplctons o Cncr
Thrpy 1461
xii SaRCOmaS Audra J. Schwalk, Saadia A. Faiz, Horiana B. Grosu,
Section Editor: Shreyaskumar Patel Lara Bashora, Vickie R. Shannon
50. Sot Tss nd Bon Srcos 1159 64. Cncr-assoctd Throboss 1493
Kelly A. Casteel, Michael H. Kroll
J. Andrew Livingston, Anthony P. Conley, Ravin Ratan,
Vinod Ravi, Shreyaskumar Patel
xiV SuPPORTiVe aND PaLLiaTiVe

xiii OTHeR TumORS aND CaNCeR CaRe
TOPiCS OF iNTeReST Section Editor: Eduardo Bruera
Section Editor: Alyssa G. Rieber
65. inptnt Spportv nd Plltv
51. endocrn mlgnncs 1189 Cr 1509
Ha Nguyen, Mouhammed Amir Habra Ahsan Azhar, Ali Haider, Eduardo Bruera
52. Th acqrd inodfcncy 66. intgrtd Otptnt

Syndro–Rltd Cncrs 1223 Spportv Cr 1519
Adan Rios, Fredrick B. Hagemeister Akhila Reddy, David Hui, Eduardo Bruera
53. Crcno o unknown Prry 1253 67. Rhbltton 1529

Gauri R. Varadhachary, Kanwal P. Raghav, Ryan W. Huey Brian Fricke, An Ngo-Huang, Ekta Gupta
54. Pdtrc Cncrs 1271 68. Pn mngnt nd Sypto

Branko Cuglievan, Wak Zaky, Richard Gorlick, Control 1553
Douglas Harrison Kaoswi K. Shih, Rony Dev, Shalini Dalal
 Contents
70. Bg D nd Mhne Lernng

xV Biostatistics n onlgy 1593
Section Editor: Xuelin Huang Peng Wei, Hai Shu
69 . sl Degn fr onlgy clnl 71. Vlue-Bed onlgy 1603

trl 1579 Casey J. Allen, Aileen Chen, Ryan W. Huey,
Ya-Chen Tina Shih
Xuelin Huang, Wei Qiao, Fang Xia, E Lin, Liang Zhu,
Jing Ning Index 1619
The fourth edition of The MD Anderson Manual of Medical Oncology is also available online as part of the excellent
accesshemonc.com website, with direct links to a comprehensive drug therapy database and to other important
medical texts that include Hematology-Oncology Therapy. The online edition of The MD Anderson Manual of Medical
Oncology also includes PubMed links to journal articles cited in the references.
New in this edition is the online-only presentation of clinical cases, The MD Anderson Manual of Medical Oncology
Cases, for readers to explore, with each case linked to the relevant chapter.
Contributors
Hind Raei, MD Joseph D. Khoury, MD

Instructor Assistant Proessor
Department o Stem Cell Transplantation and Cellular Therapy The University o Texas MD Anderson Cancer Center
Fellow, Hematology and Oncology Houston, Texas
Division o Cancer Medicine
The University o Texas MD Anderson Cancer Center Farhad Ravandi, MD
Houston, Texas Proessor
Department o Leukemia
Sergej N. Konoplev, MD, PhD The University o Texas MD Anderson Cancer Center
Associate Proessor Houston, Texas
Department o Hematopathology
The University o Texas MD Anderson Cancer Center Nitin Jain, MD
Houston, Texas Associate Proessor
Sa A. Wang, MD The University o Texas MD Anderson Cancer Center
Proessor Houston, Texas
Department o Hematopathology
Division o Pathology/Lab Medicine Philip Thompson, MD
The University o Texas MD Anderson Cancer Center Associate Proessor
Houston, Texas Department o Leukemia
The University o Texas MD Anderson Cancer Center
Nicholas J. Short, MD Houston, Texas
Assistant Proessor
Department o Leukemia Carlos Bueso-Ramos, MD, PhD
Division o Cancer Medicine Proessor
The University o Texas MD Anderson Cancer Center Department o Hematopathology
Houston, Texas The University o Texas MD Anderson Cancer Center
Houston, Texas
Hagop M. Kantarjian, MD
Proessor and Chairman Susan M. O’Brien, MD
Department o Leukemia Associate Director or Clinical Science
Samsung Distinguished University Chair in Cancer Medicine Chao Family Comprehensive Cancer Center
The University o Texas MD Anderson Cancer Center University o Caliornia Irvine
Houston, Texas Irvine, Caliornia
Elias J. Jabbour, MD William G. Wierda, MD, PhD

Department o Leukemia Proessor
Division o Cancer Medicine Department o Leukemia
The University o Texas MD Anderson Cancer Center The University o Texas MD Anderson Cancer Center
Houston, Texas Houston, Texas
Tapan M. Kadia Koji Sasaki, MD, PhD

Department o Leukemia Department o Leukemia
Division o Cancer Medicine The University o Texas MD Anderson Cancer Center
The University o Texas MD Anderson Cancer Center Houston, Texas
Houston, Texas
xi
xii Contributors
Elias Jabbour, MD Srdan Verstovsek, MD, PhD

Proessor Proessor
Department o Leukemia United Energy Resources, Inc.
The University o Texas MD Anderson Cancer Center Department o Leukemia
Houston, Texas Director, Hanns A. Pielenz Clinical Research Center or
Myeloprolierative Neoplasms (MPN)
Jorge Cortes, MD The University o Texas MD Anderson Cancer Center
Director Houston, Texas
Georgia Cancer Center at Augusta University
Medical College o Georgia Paolo Strati, MD
Augusta, Georgia Assistant Proessor
Department o Lymphoma and Myeloma
Hagop Kantarjian, MD The University o Texas MD Anderson Cancer Center
Proessor and Chairman Houston, Texas
Samsung Distinguished University Chair in Cancer Medicine Jillian R. Gunther, MD, PhD
The University o Texas MD Anderson Cancer Center Assistant Proessor
Houston, Texas Department o Radiation Oncology
Kelly Chien, MD Houston, Texas
Department o Leukemia L. Jerey Medeiros, MD
The University o Texas MD Anderson Cancer Center Proessor
Houston, Texas Department o Hemato-Pathology
Carlos Bueso-Ramos, MD, PhD Houston, Texas
Proessor
Department o Hematopathology Loretta J. Nastoupil, MD
The University o Texas MD Anderson Cancer Center Associate Proessor
Houston, Texas Department o Lymphoma and Myeloma
Guillermo Garcia-Manero, MD Houston, Texas
Proessor
Chie, Section o Myelodysplastic Syndromes Felipe Samaniego, MD
Department o Leukemia Department o Lymphoma and Myeloma
Prithviraj Bose, MD Raphael Steiner, MD

Associate Proessor Assistant Proessor
Lucia Masarova, MD Jason R. Westin, MD

Assistant Proessor Associate Proessor
Hesham M. Amin, MD, MSc Sergej N. Konoplev, MD, PhD

Proessor Associate Proessor
Department o Hematopathology Department o Hematopathology
Contributors xiii
Luis E. Fayad, MD Gregory P. Kauman, MD

Proessor Assistant Proessor
Department o Lymphoma and Myeloma Department o Lymphoma and Myeloma
Preetesh Jain, MBBS, MD, DM, PhD Muzaar H. Qazilbash, MD

Assistant Proessor Proessor
Department o Lymphoma and Myeloma Department o Stem Cell Transplantation and Cellular Therapy
Mantle Cell Lymphoma Program o Excellence The University o Texas MD Anderson Cancer Center
Houston, Texas
Krina Patel, MD
Michael Wang, MD Associate Proessor
Proessor Department o Lymphoma and Myeloma
Department o Lymphoma/Myeloma The University o Texas MD Anderson Cancer Center
Houston, Texas
Sheeba Thomas, MD
Ranjit Nair, MD Proessor
Assistant Proessor Department o Lymphoma and Myeloma
Department o Lymphoma and Myeloma The University o Texas MD Anderson Cancer Center
Houston, Texas
Robert Z. Orlowski, MD, PhD
Francisco Vega, MD, PhD Proessor
Department o Hematopathology The University o Texas MD Anderson Cancer Center
Houston, Texas
Elisabet E. Manasanch, MD, MHSc
Swaminathan P. Iyer, MD Associate Proessor
Department o Lymphoma and Myeloma The University o Texas MD Anderson Cancer Center
Houston, Texas
Paul Lin
Auris Huen, PharmD, MD Assistant Proessor
Associate Proessor Department o Stem Cell Transplantation and Cellular Therapy
Department o Dermatology The University o Texas MD Anderson Cancer Center
Houston, Texas
Hans C. Lee, MD
Collin K. Chin, MBBS Assistant Proessor
Bloodwise Clinic Department o Lymphoma and Myeloma
Perth, Australia The University o Texas MD Anderson Cancer Center
Houston, Texas
Fredrick B. Hagemeister
Department o Lymphoma and Myeloma Melody Becnel, MD
Hun J. Lee Houston, Texas
The University o Texas MD Anderson Cancer Center Donna Weber
Houston, Texas
xiv Contributors
Sairah Ahmed Samer A. Srour, MB ChB, MS

Department o Lymphoma and Myeloma Assistant Proessor
The University o Texas MD Anderson Cancer Center Department o Stem Cell Transplantation and Cellular Therapy
Houson, Texas
Simrit Parmar
Department o Lymphoma and Myeloma Richard E. Champlin, MD
The University o Texas MD Anderson Cancer Center Chairman
Houston, Texas Department o Stem Cell Transplantation and Cellular Therapy
Sattva Neelapu Houston, Texas
The University o Texas MD Anderson Cancer Center Stean O. Ciurea, MD
Department o Stem Cell Transplantation and Cellular Therapy
Neeraj Saini, MD The University o Texas MD Anderson Cancer Center
Assistant Proessor Houston, Texas;
Department o SCT and Cellular Therapy Proessor, Director o the Hematopoietic Stem Cell
Department o Lymphoma and Myeloma Transpalntation and Cellualr Therapy Program
The University o Texas MD Anderson Cancer Center University o Caliornia, Irvine, Caliornia
Houston, Texas
Amanda Olson, MD
Yago Nieto, MD Associate Proessor
Proessor Department o Stem Cell Transplantation and Cellular Therapy
Department o SCT and Cellular Therapy The University o Texas MD Anderson Cancer Center
Houston, Texas
Jeremy Ramdial
Rohtesh S. Mehta, MD, MPH, MS Assistant Proessor
Assistant Proessor Department o Stem Cell Transplantation and Cellular Therapy
Department o Stem Cell Transplantation and Cellular Therapy The University o Texas MD Anderson Cancer Center
Division o Cancer Medicine Houston, Texas
Houston, Texas Uri Greenbaum
Chitra Hosing, MD The University o Texas MD Anderson Cancer Center
Proessor Houston, Texas
Houston, Texas Partow Kebriaei
Proessor
Betul Oran, MD Department o Stem Cell Transplantation and Cellular Therapy
Associate Proessor The University o Texas MD Anderson Cancer Center
Department o Stem Cell Transplantation and Cellular Therapy Houston, Texas
The University o Texas MD Anderson Cancer Center Jeremy A. Ross, MD
Houston, Texas Medical Oncologist
Center or Cancer and Blood Disorders
Katayoun Rezvani, MD, PhD Fort Worth, Texas
Proessor
Department o Stem Cell Transplantation and Cellular Therapy Lauren A. Byers, MD
Division o Cancer Medicine Proessor
The University o Texas MD Anderson Cancer Center Department o Thoracic/Head and Neck Medical Oncology
Houston, Texas Division o Cancer Medicine
Elizabeth J. Shpall, MD Houston, Texas
Proessor
Houston, Texas
Contributors xv
Carl M. Gay, MD, PhD Amy Moreno, MD

Assistant Proessor Assistant Proessor
Department o Thoracic/Head and Neck Medical Oncology Department o Radiation Oncology, Head and Neck Service
Division o Cancer Medicine The University o MD Anderson Cancer Center
Houston, Texas
Frank Mott, MD, FACP
Mehmet Altan Proessor
Department o Thoracic/Head and Neck Medical Oncology Department o Thoracic/Head and Neck Medical Oncology
Division o Cancer Medicine The University o MD Anderson Cancer Center
Houston, Texas
Mariela Blum Murphy
Joshua M. Gulvin, MD Department o Gastrointestinal Medical Oncology
Hematology/Oncology The University o Texas MD Anderson Cancer Center
St. Charles Health System Houston, Texas
Redmond, OR
Elena Elimova, MD
George Simon, MD Medical Oncologist
Executive Director, Clinical Research Unit Princess Margaret Cancer Centre
Mott Cancer Center-Advent Health Toronto, ON
Celebration, FL
Ahmed Abdelhakeem, MD
Bonnie Glisson Internal Medicine Resident
Department o Thoracic/Head and Neck Medical Oncology Department o Medicine
The University o Texas MD Anderson Cancer Center Jaer Ajani
Houston, Texas Department o Gastrointestinal Medical Oncology
Yasir Y. Elamin Houston, Texas
Department o Thoracic / Head and Neck Medical Oncology Jonathan D. Mizrahi, MD
Houston, Texas Department o Hematology and Oncology
The Oschner Clinic
Don L. Gibbons
Proessor Anirban Maitra, MBBS
Department o Thoracic / Head and Neck Medical Oncology; Proessor
Department o Molecular and Cellular Oncology Department o Anatomical Pathology
Marcelo V. Negrao Robert A. Wol, MD

Department o Thoracic / Head and Neck Medical Oncology Department o GI Medical Oncology
Ruth Sacks, MD Shalini Makawita, MD

Assistant Proessor Medical Oncologist
Department o Hematology and Medical Oncology Baylor College o Medicine
Winship Cancer Center o Emory University Houston, Texas
Atlanta, Georgia
Sunyoung Lee, MD, PhD
David Boyce-Fappiano, MD Assistant Proessor
Resident Physician Department o Gastrointestinal Medical Oncology
Department o Radiation Oncology Division o Cancer Medicine
The University o MD Anderson Cancer Center The University o Texas MD Anderson Cancer Center
xvi Contributors
Yun Shin Chun, MD, FACS Rony Avritscher

Associate Proessor Proessor
Department o Surgical Oncology Department o Interventional Radiology
Division o Surgery The University o Texas MD Anderson Cancer Center
Houston, Texas
Ahmed O. Kaseb
Millicent A. Roach, BS Proessor
Assistant Clinical Research Coordinator Department o Gastrointestinal Medical Oncology
Department o Radiation Oncology The University o Texas MD Anderson Cancer Center
Division o Radiation Oncology Houston, Texas
Houston, Texas Pat Gulhati, MD, PhD
Eugene J. Koay, MD, PhD Cancer Institute o New Jersey
Associate Proessor Rutgers University
Department o Radiation Oncology
Division o Radiation Oncology John Paul Shen
The University o Texas MD Anderson Cancer Center Department o Gastrointestinal Medical Oncology
Houston, Texas
Milind Javle, MD
Proessor Michael J. Overman
Department o Gastrointestinal Medical Oncology Department o Gastrointestinal Medical Oncology
Houston, Texas
Arvind Dasari, MD, MS
Sunyoung S. Lee Associate Proessor
Proessor Department o Gastrointestinal Medical Oncology
Department o Gastrointestinal Medical Oncology The University o Texas MD Anderson Cancer Center
Houston, Texas
Benny Johnson, DO
Hao Chi Zhang Assistant Proessor
Assistant Proessor Department o Gastrointestinal Medical Oncology
Department o Gastroenterology, Hepatology, and Nutrition, The University o Texas MD Anderson Cancer Center
Houston, Texas
Christine Parseghian, MD
Hop S. Tran Cao Assistant Proessor
Associate Proessor Department o Gastrointestinal Medical Oncology
Department o Surgical Oncology The University o Texas MD Anderson Cancer Center
Houston, Texas
Kanwal P. Raghav, MD
Sudha Kodali Associate Proessor
Transplant Hepatology, Houston Methodist Hospital Department o Gastrointestinal Medical Oncology
Houston, Texas
Joshua D. Kuban
Associate Proessor Scott Kopetz, MD, PhD
Department o Interventional Radiology Proessor and Deputy Chair
The University o Texas MD Anderson Cancer Center Department o Gastrointestinal Medical Oncology
Houston, Texas
Eugene J. Koay
Associate Proessor Emma Holliday, MD
Department o Radiation Oncology Department o Radiation Oncology
Contributors xvii
Van Morris, MD Bora Lim, MD

Department o Medical Oncology Associate Proessor
The University o Texas MD Anderson Cancer Center Department o Medicine-Oncology
Houston, Texas Baylor College o Medicine
Houston, Texas
Craig A. Messick, MD, FACS, FASCRS
Associate Proessor Gabriel N. Hortobagyi, MD, FACP
Department o Colon and Rectal Surgery; Proessor
Department o Surgical Oncology Department o Breast Medical Oncology
Jessica E. Maxwell, MD, MBA Rachel M. Layman, MD

Department o Surgical Oncology The University o Texas MD Anderson Cancer Center
Houston, Texas
Roni Nitecki, MD, MPH
James C. Yao, MD Clinical Fellow
Proessor and Chair Department o Gynecologic Oncology and Reproductive
Department o Gastrointestinal Medical Oncology Medicine
Daniel M. Halperin, MD Lauren P. Cobb, MD

Department o Gastrointestinal Medical Oncology Department o Gynecologic Oncology and Reproductive
The University o Texas MD Anderson Cancer Center Medicine
Houston, Texas
Demetria Smith-Graziani, MD
Fellow, Hematology and Medical Oncology J. Alejandro Rauh-Hain, MD, MPH
The University o Texas MD Anderson Cancer Center; Instructor Assistant Proessor
Department o Medicine, Section o Hematology and Oncology, Gynecologic Oncology and Reproductive Medicine
Baylor College o Medicine The University o Texas MD Anderson Cancer Center
Mariana Chavez-MacGregor, MD Amir A. Jazaeri, MD

Associate Proessor Proessor
Department o Health Services Research Department o Gynecologic Oncology
Haven R. Garber, MD, PhD Michaela A. Onstad, MD, MPH

Department o Breast Medical Oncology Gynecologic Oncology and Reproductive Medicine
Meghan S. Karuturi, MD Shannon N. Westin, MD, MPH

Associate Proessor Associate Proessor
Department o Breast Medical Oncology Department o Gynecologic Oncology and Reproductive
The University o Texas MD Anderson Cancer Center Medicine
Houston, Texas
Gabriel N. Hortobagyi, MD, FACP
Proessor
Department o Breast Medical Oncology
Houston, Texas
xviii Contributors
Karen H. Lu, MD Jose A. Karam, MD, FACS

Chair and Proessor Associate Proessor
Department o Gynecologic Oncology and Reproductive Department o Urology
Medicine Division o Surgery and Department o Translational Molecular
The University o Texas MD Anderson Cancer Center Pathology
Houston, Texas Division o Pathology and Laboratory Medicine
Gloria Salvo, MD Houston, Texas
Clinical Research
Department o Gynecologic Oncology and Reproductive Christopher G. Wood, MD, FACS
Medicine Proessor
The University o Texas MD Anderson Cancer Center Deputy Chairman, Department o Urology
Houston Texas The University o Texas MD Anderson Cancer Center
Houston, Texas
Mila P. Salcedo, MD
Visiting Scientist Nizar M. Tannir, MD, FACP
Department o Gynecologic Oncology and Reproductive Proessor
Medicine Department o Genitourinary Medical Oncology
The University o Texas MD Anderson Cancer Center, Houston, Division o Cancer Medicine
Texas; Associate Proessor, Chair o Gynecology The University o Texas MD Anderson Cancer Center
The Obstetrics and Gynecology Department, Federal University Houston, Texas
o Health Sciences o Porto Alegre/Santa Casa de Misericordia
o Porto Alegre Hospital, Brazil Alexander Y. Andreev-Drakhlin, MD, PhD
Genentech, San Francisco, Caliornia
Sol Basabe, MD
Postdoctoral Fellow Arlene O. Sieker-Radtke, MD
Medicine, Department o Genitourinary Medical Oncology
Pedro T. Ramirez, MD Ashish M. Kamat, MD

Proessor, Editor-in-Chie Proessor
International Journal o Gynecological Cancer, David M. Department o Urology
Gershenson Distinguished Proessor in Ovarian Cancer The University o Texas MD Anderson Cancer Center
Research, Director o Minimally Invasive Surgical Research Houston, Texas
and Education, Department o Gynecologic Oncology and
Reproductive Medicine Patrick Pilié, MD
Houston, Texas Department o GU Medical Oncology
Han T. Cun, MD Houston, Texas
Clinical Fellow
Department o Gynecologic Oncology and Reproductive Paul Viscuse, MD
Medicine Clinical Fellow
The University o Texas MD Anderson Cancer Center Division o Cancer Medicine
Houston, Texas
Aaron Shaer, MD
Associate Proessor Christopher J. Logothetis, MD
Medicine Department o GU Medical Oncology
Andrew W. Hahn, MD Paul G. Corn, MD

Medical Oncology Fellow Proessor
Division o Cancer Medicine Department o GU Medical Oncology
Contributors xix
Jad Chahoud, MD, MPH Houssein Saa, MD

GU Department, Mott Cancer Center, Tampa, Florida Internal Medicine Resident
Montefore Health System
Curtis A. Pettaway, MD Bronx, New York
Urology Department
The University o Texas MD Anderson Cancer Center Jane Mattei
Houston, Texas Clinical Fellow
Department o Melanoma Medical Oncology
Joseph A. Moore, MD The University o Texas MD Anderson Cancer Center
Sta Oncologist Houston, Texas
Cancer Center o Kansas
Wichita, Kansas Andrew J. Bishop, MD, AM
Shi-Ming Tu, MD Department o Surgical Oncology
Proessor The University o Texas MD Anderson Cancer Center
Department o GU Medical Oncology Houston, Texas
Houston, Texas Emily Z. Keung, MD
Shiao-Pei Weathers, MD Department o Surgical Oncology
Assistant Proessor The University o Texas MD Anderson Cancer Center
Department o Neuro-Oncology Houston, Texas
Division o Cancer Medicine; Clinical Medical Director, Brain and
Spine Center Sirisha Yadugiri, PhD, MHA
The University o Texas MD Anderson Cancer Center Sr. Technical Writer, Department o Melanoma Medical Oncology
Houston, Texas
Barbara O’Brien, MD
Assistant Proessor Michael A. Davies, MD, PhD
Department o Neuro-Oncology Proessor and Chair
Division o Cancer Medicine Department o Melanoma Medical Oncology
The University o Texas MD Anderson Cancer Center Proessor, Translational Molecular Pathology, Genomic Medicine,
Houston, Texas Systems Biology, Anne and John Mendelsohn Chair in Cancer
Research
Ashley Aaroe, MD The University o Texas MD Anderson Cancer Center
Clinical Fellow, Department o Neuro-Oncology Houston, Texas
The University o Texas MD Anderson Cancer Center Isabella C. Glitza Oliva
Houston, Texas Department o Melanoma Medical Oncology
Debra Yeboa, MD Houston, Texas
Department o Radiation Oncology J. Andrew Livingston, MD
Division o Radiation Oncology Assistant Proessor
The University o Texas MD Anderson Cancer Center Department o Sarcoma Medical Oncology
Houston, Texas
Sujit Prabhu, MD, FRCS (Ed)
Proessor Anthony P. Conley
Department o Neurosurgery Associate Proessor
Division o Surgery Department o Sarcoma Medical Oncology
John de Groot, MD Ravin Ratan, MD

Department Chair ad interim, Department o Neuro-Oncology Department o Sarcoma Medical Oncology
Houston, Texas
xx Contributors
Vinod Ravi, MD Jason A. Willis, MD

Associate Proessor Assistant Proessor
Department o Sarcoma Medical Oncology Department o GI Medical Oncology (or Gastrointestinal Medical
The University o Texas MD Anderson Cancer Center Oncology)
Houston, Texas
Shreyaskumar Patel, MD
Proessor Jennier B. Goldstein, MD, PhD
Department o Sarcoma Medical Oncology Medical Oncologist
The University o Texas MD Anderson Cancer Center University o Caliornia-Irvine
Houston, Texas Irvine, Caliornia
Ha Nguyen, MD Zhijing Zhang

Assistant Proessor College Student
Department o Medicine Department o Genomic Medicine
Baylor College o Medicine The University o Texas MD Anderson Cancer Center
Mouhammed Amir Habra, MD Andy Futreal

Proessor Department o Genomic Medicine
Department o Endocrine Neoplasia The University o Texas MD Anderson Cancer Center
Houston, Texas
Bilal A. Siddiqui, MD
Adan Rios, MD Assistant Proessor
Associate Proessor Department o Genitourinary Medical Oncology
Division o Medical Oncology The University o Texas MD Anderson Cancer Center
The University o Texas Health Science Center-Houston Houston, Texas
Houston, Texas
Sangeeta Goswami, MD, PhD
Gauri R. Varadhachary, MD† Assistant Proessor
Proessor Departments o Genitourinary Medical Oncology and
Department o GI Medical Oncology Immunology
Branko Cuglievan, MD James P. Allison, PhD

Assistant Proessor Chair and Regental Proessor, Department o Immunology, MD
Section Chie ad Interim, Pediatric Leukemia, and Lymphoma Anderson Cancer Center
Wafk Zaky, MD Padmanee Sharma, MD, PhD

Associate Proessor Proessor, Departments o Genitourinary Medical Oncology and
Department o Pediatrics Immunology
Richard Gorlick, MD Rabih Said, MD, MPH

Proessor Associate Proessor, Oncology Division, St George Hospital
Division Head and Department Chair, University Medical Center, University o Balamand, Beirut,
Department Chair ad interim, Sarcoma Medical Oncology Lebanon
Houston, Texas Apostolia-Maria Tsimberidou, MD, PhD
Proessor
Douglas Harrison, MD, MS Department o Investigational Cancer Therapeutics
Associate Proessor The University o Texas MD Anderson Cancer Center
Center Medical Director Houston, Texas
Houston, Texas
Contributors xxi
Fareed Khawaja, MD Sai-Ching Jim Yeung

Department o Inectious Diseases Department o Emergency Medicine
Roy F. Chemaly, MD Ellen F. Manzullo, MD, FACP

Department o Inectious Diseases Deputy Division Head (Clinical) Internal Medicine
Bruno P. Granwehr, MD, MS, FACP, CMQ Patrick Chatari, MD, MBA, FACP
Department o Inectious Diseases Department o Emergency Medicine
The University o Texas MD Anderson Cancer Center Clinical Medical Director, Clinical Decision Unit (CDU)
Houston, Texas
Dimitrios P. Kontoyiannis, MD, ScD, PhD(Hon.), FACP,
FIDSA, FECMM, FAAM, FAAAS Elie Mouhayar, MD, FACC, FSVM
Department o Inectious Diseases, Texas 4000, Distinguished Department o Cardiology.
Endowed Proessor or Cancer Research, Deputy Head The University o Texas M. D. Anderson Cancer Center
Division o Internal Medicine Houston, Texas
Houston, Texas Danielle El-Haddad, MD
Clinical research resident, Department o Cardiology.
Rachael Hosein, MD The University o Texas M. D. Anderson Cancer Center
Aurora Health Care, 2414 Kohler Memorial Dr, Sheboygan, Houston, Texas
Wisconsin; Division o Endocrinology, Diabetes, and
Metabolism, McGovern Medical School Peter Kim, MD
The University o Texas Health Science Center Associate Proessor
Houston, Texas Department o Cardiology.
The University o Texas M. D. Anderson Cancer Center
Sara Bedrose, MD Houston, Texas
Department o Endocrinology, Diabetes and Metabolism, Baylor
College o Medicine Kara Thompson, MD
Department o Cardiology.
Rebecca Jeun, MD The University o Texas M. D. Anderson Cancer Center
Department o Endocrinology, Diabetes and Metabolism, Baylor Houston, Texas
College o Medicine
Houston, Texas Cezar Iliescu, MD
Proessor
Sonali N. Thosani, MD Department o Cardiology.
Associate Proessor The University o Texas M. D. Anderson Cancer Center
Department o Endocrine Neoplasia and Hormonal Disorders Houston, Texas
Section Chie, Diabetes and Metabolic Disorders
Certifed in Medical Quality (CMQ) Kaoswi K. Shih, MD
Division o Internal Medicine Quality Council, Chair Assistant Proessor
Patient Saety and Quality Ocer, Endocrine Department Palliative Care Medicine
The University o Texas MD Anderson Cancer Center University o Texas MD Anderson Cancer Center
Jeena M. Varghese, MD Rony Dev, MD

Endocrine Neoplasia and Hormonal Disorders Palliative Care Medicine
The University o Texas MD Anderson Cancer Center University o Texas MD Anderson Cancer Center
xxii Contributors
Shalini Dalal, MD Ahsan Azhar, MD

Palliative Care Medicine Palliative, Rehabilitation and Integrative Medicine Department
University o Texas MD Anderson Cancer Center The University o Texas MD Anderson Cancer Center
Abdulrazzak Zaria, MD Eduardo Bruera, MD

Department o Cardiology. Proessor and Chair, Palliative, Rehabilitation and Integrative
The University o Texas M. D. Anderson Cancer Center Medicine Department
Houston, Texas
Audra J. Schwalk, MD
Assistant Proessor Akhila Reddy, MD
Department o Internal Medicine-Pulmonary and Critical Care Associate Proessor
Medicine Department o Palliative, rehabilitation, and Integrative Medicine
University o Southwestern Medicine Center The University o Texas MD Anderson Cancer Center
Dallas, Texas Houston, Texas
Saadia A. Faiz, MD David Hui, MD

Department o Pulmonary Medicine Department o Palliative, Rehabilitation, and Integrative Medicine
Horiana B. Grosu, MD Brian Fricke, MD

Associate Proessor Fellow, Department o Palliative, Rehabilitation, and Integrative
Department o Pulmonary Medicine Medicine
Lara Bashora, MD An Ngo-Huang, DO

Vickie R. Shannon, MD Ekta Gupta, MD

Kelly A. Casteel Xuelin Huang, PhD

Department o Benign Hematology Deputy Chair, Department o Biostatistics
Michael H. Kroll, MD Wei Qiao, PhD

Proessor Senior Biostatistician, Department o Biostatistics
Department o Benign Hematology The University o Texas MD Anderson Cancer Center
Houston, Texas
Fang Xia, PhD
Ali Haider, MD Biostatistics Manager, Gilead Sciences, Foster City, Caliornia
Department o Palliative, Rehabilitation and Integrative Medicine E Lin, MD, PhD
Department Associate Director o Biostatistics, PTC Therapeutics, Inc., South
The University o Texas MD Anderson Cancer Center Plainfeld, New Jersey
Houston, Texas
Contributors xxiii
Liang Zhu, PhD Aileen Chen, MD, MPP

Associate Proessor, Department o Internal Medicine Associate Proessor
The University o Texas Health Science Center at Houston Department o Radiation Oncology and Department o Health
Houston, Texas Services Research
Jing Ning, PhD Houston, Texas
Associate Proessor
Department o Biostatistics Ryan W. Huey, MD
Houston, Texas Department o Gastrointestinal Medical Oncology
Peng Wei, PhD The University o Texas MD Anderson Cancer Center
Department o Biostatistics Houston, Texas
Houston, Texas Ya-Chen Tina Shih, PhD
Proessor
Hai Shu, PhD Department o Health Services Research, Chie, Section o Cancer
Department o Biostatistics, School o Global Public Health, New Economics and Policy
York University, New York, New York Division o Cancer Prevention and Population Sciences
Casey J. Allen, MD Houston, Texas
Fellow, Department o Surgical Oncology
Division o Surgery
Houston, Texas
A Brief History
of MD Anderson
Cancer Center
Houston’s evolution into the ourth largest city in the The charter o the Anderson
United States was propelled by our seminal events. Foundation did not speciy
First was the Great Galveston Hurricane o 1900, how the money should be
which destroyed the city port o Galveston and led to used, but Mr. Anderson’s
the realization that Houston could become a viable and trustees and close riends—
saer deep-water port; this led to the widening o the Colonel William Bates,
Ship Channel to oer direct access to Houston. Second John Freeman and Horace
was the discovery o oil at Spindletop in Beaumont, Williams—leaned strongly
Texas in 1901. This prompted the development o the in avor o health care. Soon
oil industry in Texas and transormed Houston rom ater taking possession o the
a small town into a large city. Third was (o course) estate rom its executors, the
the commercialization o air conditioning in 1950’s, FiGURe 2. trustees turned to Dr. Ernest
which made Houston (and many Southern cities o the Bertner (Fig. 2) or advice. Dr.
United States) more livable. And lastly, the allocation Bertner was a prominent Houston surgeon and gyne-
o land or the Texas Medical Center created the larg- cologist who was well known to the trustees because
est medical center in the world with one o the high- o his care or cancer patients, despite inadequate
est densities o clinical acilities or patient care, basic acilities and treatment options (he was later called the
science, and translational research. The Texas Medical “ather o the Texas Medical Center”).
Center is a major contributor to Houston’s economy The trustees and Dr. Bertner noted that the 1941
and growth. Texas legislature authorized the University o Texas
Several additional actors contributed to the cre- to create a hospital or cancer research and treat-
ation o The University o Texas MD Anderson Cancer ment, allocating $500,000 or the purpose. Today,
Center in Houston and its that gure would be approximately $8 million. The
development into one o the Anderson trustees, with Dr. Bertner’s guidance,
most important cancer cen- seized the opportunity and oered to match the
ters in the world. First was $500,000 legislative appropriation, i the hospital
the generous philanthropy was to be named or Monroe Dunaway Anderson
o visionary Texans such as and located in Houston. The legislature accepted
Monroe Dunaway Anderson their oer. The trustees then purchased 134 acres o
(Fig. 1) (his nephew died o mosquito-inested land to create the Texas Medical
leukemia in 1936) and his Center, stating that the new cancer hospital would
partner Will Clayton, who be located there. They made it known that the new
ounded the charitable MD state hospital should be an academic institution. In
Anderson Foundation, which act, MD Anderson was the rst comprehensive can-
FiGURe 1. helped create the Texas cer hospital to be associated with a major university
Medical Center in 1945. as an independent ree-standing unit.
v
v A Brif History of MD Adrso Cacr Ctr
In 1942, The University o Texas Board o Regents carriage house became the oce and stables were the
appointed Dr. Bertner as the director o the new hospi- research laboratories. Twelve surplus army barracks
tal. A 6-acre property near downtown was purchased were procured or patient clinics (Figs. 3A-C). With
rom the estate o Captain James A. Baker, granda- the addition o 22 leased beds at Hermann Hospital,
ther o ormer Secretary o State James Baker III, and the dream became realityA small aculty o physi-
became the rst campus o the hospital. An empty cians and scientists was recruited rom the University
FiGURe 3A.
FiGURe 3B.
A Brif History of MD Adrso Cacr Ctr v
FiGURe 3c.
o Texas Medical Branch in Galveston, and cancer In 1946, Dr. Bertner persuaded Dr. Randolph Lee
patients nally had a home. The name proposed in Clark, a native Texan, to become president o what
1941 was the “Texas State Cancer Hospital and the was to become The University o Texas MD Anderson
Division o Cancer Research”, which was changed to Cancer Center. Dr. Clark, a widely recognized surgeon,
“M.D. Anderson Hospital or Cancer Research o The concentrated on recruiting an excellent surgical aculty
University o Texas” (to acknowledge the donation o and then set upon acquiring all the basic and clinical
M.D. Anderson). The name was again changed in 1955 scientists and clinicians. From the outset, all eorts,
to “The University o Texas M.D. Anderson Hospital whether administrative, clinical or research, were
and Tumor Institute at Houston” ( to avoid the word ocused on developing excellence in research-driven
“cancer” which elicited ear and avoidance). In 1988 cancer care. Forty-six patients were receiving treat-
the name was nally changed to its current “The ment in these early quarters when the hospital moved
University o Texas MD Anderson Cancer Center”. to its current site in March 1954 (Figs. 4A and B).
FiGURe 4A. FiGURe 4B.

v A Brif History of MD Adrso Cacr Ctr
FiGURe 5.
Additional resources to the No. 1 hospital or cancer

expand the MD Anderson care by the U.S. News and
inra-structure (Fig. 5) and World Report in 11 o the past
research capacities came 14 years. The MD Anderson
rom several venues: (1) gen- Cancer Center research has
erous donations rom the resulted in numerous discov-
oil industry; (2) the vision- eries that became standards o
ary research and administra- care across many types o can-
tive leadership under its ve cers, and that have saved the
presidents, Drs. Randolph lives and/or improved surviv-
Lee Clark (1946–1978) (Fig. als and outcomes o millions
FiGURe 6A. FiGURe 6D.
6A), Charles A. LeMaistre o patients with cancer around
(1978–1996) (Fig. 6B), John the world.
Mendelsohn (1996–2011) (Fig. One component o MD
6C), Ronald DePinho (2011– Anderson’s mission is to
2017) (Fig. 6D), and Peter WT spread its knowledge about
Pisters (2017-present) (Fig. 6E); cancer research and discover-
(3) the recruitment o world- ies across the globe. This edu-
renowned cancer research cational mission is urthered
pioneers (some o the early by the hematology/oncol-
legends included Drs. Emil J. ogy ellowship that currently
Freireich, Emil Frei, Gilbert trains more than 40 medical
Fletcher, James Butler, Felix hematology-oncology cancer
FiGURe 6B. Rutledge, Gerald Dodd, and FiGURe 6e. specialists on its premises.
Sidney Wallace); and (4) the The MD Anderson Manual of
relentless research eorts o Medical Oncology, created as part o our educational
the cancer experts on the MD mission, is oten written by our ellows as rst authors
Anderson’s aculty. ( many o whom later join the MD Anderson aculty)
Today, MD Anderson is and supported in depth by senior tumor specialty ac-
one o the largest cancer cen- ulty as co-authors. We envision this ourth edition
ters in the world, with more expanding into a continuously updated electronic ver-
than 21,000 employees and sion that educates and spreads knowledge and discov-
1800 aculty; serving more eries in cancer research and therapy rapidly and widely.
than 150,000 patients with
cancer in Houston every year; Hagop M. Kantarjian, MD
operating a 700-bed cancer Robert A. Wolff, MD
FiGURe 6c.
hospital; and being ranked as Alyssa G. Reiber, MD
Foreword
The MD Anderson Manual of Medical Oncology, ourth extraordinary wealth o inormation brought about
edition, articulates the personalized, multidisciplinary by big data analytics and its application to infuence
approach to cancer management pioneered by The value-based oncology care. Supportive and Palliative
University o Texas MD Anderson Cancer Center. Care content refects current approaches in advanced
Our unique perspective has evolved rom decades o symptom management concurrent with a patient’s
clinical practice and research with more than 1.6 mil- entire cancer journey, starting at diagnosis.
lion patients turning to MD Anderson or care. We are Every chapter includes abundant tables and dia-
expanding our reach, making it easier or the patients grams, including algorithms and decision trees devel-
and communities we serve to access our expertise. oped at MD Anderson or specic cancers or disease
We are enabling high-impact discovery and introduc- subtypes; promising novel therapy targets and the lat-
ing novel therapies through a leading clinical trials est clinical trial phase o drugs targeting them; and new
network. And we are setting new standards or high- molecular therapies recommended to overcome resis-
touch, high-value cancer care. tance to previously eective therapies.
This book is designed to bring a pragmatic approach Emphasis on saety is even more relevant now than
to cancer management that may serve as a guide or in prior editions o this book. MD Anderson’s core
oncologists around the world. The text refects how value o Saety drives our colleagues each day, and
MD Anderson currently operates, including many this was especially highlighted during the COVID-
patient care practices that would not have been rec- 19 pandemic when we came together with diligence,
ognized by practitioners just a decade ago. Since the determination and evidence-based protocols to ensure
rst edition, MD Anderson’s experts have improved the saest possible environment or our immuno-
our ability to identiy biomarkers that are predictive compromised patients. Additionally, we remain laser
or survival, a major triumph in medical oncology that ocused on survivorship, as advances in cancer care
is demonstrated throughout the text. have increased the number o people who are cancer
Refecting new advances in our research and our ree or who are living with cancer as a chronic con-
approach to cancer management, the ourth edition o dition rather than a atal one. We remain dedicated
The MD Anderson Manual of Medical Oncology eatures to our bold aspiration o maximizing our impact on
a wealth o new material. The sections on Lymphoma humanity through research-driven patient care, educa-
and Myeloma and Gastrointestinal Cancer contain tion, prevention and science that contribute to Making
additional chapters ocused on recently dened sub- Cancer History®.
sets o disease and their treatment modalities. New
targeted therapies are described in Lung Cancer. Peter WT Pisters, MD, MHCM
Additional Cancer Topics o Interest chapters detail President, The University o Texas MD Anderson
updated knowledge in viral and ungal inections, or Cancer Center
example, as well as oncocardiology and thrombosis. Houston, Texas
Biostatistics now has its own section, underscoring the January, 2022

Preface
When we rst envisioned The MD Anderson Manual The new edition o The MD Anderson Manual
of Medical Oncology, we hoped that it would ll an of Medical Oncology contains new chapters on cord
important void in oncology reerence material by serv- blood transplant, haploidentical stem cell transplan-
ing as a hands-on resource or the practicing oncolo- tation, cellular therapy in allogeneic hematopoietic
gist. The rst edition, published in 2006, was written cell transplantation, pediatric cancers, molecular
exclusively by our aculty and ellows with the idea o biomarkers and cancer, immuno-oncology, targeted
giving a bird’s-eye view o how multidisciplinary care therapies in cancer, applied biostatistics, oncocardi-
was practiced at our institution. We were proud o that ology, pulmonary complications o cancer therapy,
initial eort and pleased that the book received posi- and cancer-associated thrombosis. In addition, there
tive reviews rom several high-impact journals, includ- is expanded coverage o the rapidly growing areas o
ing JAMA, The Lancet, and The New England Journal of biological and immune therapies o cancer, with one
Medicine. chapter co-authored by our very own Nobel Laureate,
The second edition, published in 2011, moved closer Jim Allison.
to the aims o providing more illustrations, gures, The new edition o The MD Anderson Manual of
tables, and algorithms. In addition, the second edition Medical Oncology will also be a continually updated
included new chapters on myelodysplastic syndromes, version o the book, online, with the latest science and
Philadelphia chromosome-negative myeloprolierative clinical recommendations rom the world-renowned
neoplasms, T-cell lymphomas, small bowel cancer and clinical investigators at MD Anderson.
appendiceal tumors, infammatory breast cancer, and We hope that this edition serves to help oncologists
penile cancer. everywhere provide high-quality, state-o-the-art can-
In the third edition, we have continued the tradition cer care to their patients.
o including evidence-based management algorithms
in the orm o fowcharts and diagrams, shaped by the Hagop M. Kantarjian, MD
clinical experience o our world-class aculty at MD Robert A. Wol, MD
Anderson. Readers are also provided with a practical Alyssa G. Reiber, MD
guide to the diagnostic and therapeutic strategies used
at MD Anderson.

Section I Leukemia
Section Editor: William G. Wierda
1 Acute Lymphoblastic Leukemia
2 Adult Acute Myeloid Leukemia
3 Chronic Lymphocytic Leukemia and Associated Disorders
4 Chronic Myeloid Leukemia
5 Myelodysplastic Syndromes: The MD Anderson Cancer Center

Approach
6 Philadelphia Chromosome–Negative Myeloproliferative

Neoplasms
1 Acute Lymphoblastic Leukemia
Hind Rafei
Sergej N. Konoplev
Sa A. Wang
Nicholas J. Short
Hagop M. Kantarjian
Elias J. Jabbour
KEY CONCEPTS
 Acute lymphoblastic leukemia (ALL) is classied into B-cell methotrexate and cytarabine) or allogeneic hematopoi-
ALL, T-cell ALL, and natural killer cell ALL. Cytogenetics are etic stem cell transplant. Maintenance consists o POMP
key in the diagnosis o ALL because they hold a predictive (Purinethol, Oncovin, methotrexate, and prednisone) or
and prognostic value. A Philadelphia chromosome–like DOMP (Dexamethasone, Purinethol, Oncovin, and metho-
signature that lacks the expression o BCR-ABL1 usion pro- trexate) chemotherapy or 2 to 3 years. Clinical trials are
tein but does have a gene expression prole similar to BCR- evaluating the use o novel agents, such as antibody–
ABL1+ ALL has been recently dened. drug conjugates and bispecic antibodies, in the rontline
 Measurement o measurable residual disease (MRD) using setting.
multiparameter fow cytometry, quantitative polymerase  The combination o chemoimmunotherapy is the main-
chain reaction, and next-generation sequencing is stan- stay o treatment o patients with ALL and is a eld o
dard o care in the treatment o patients with ALL, and it ongoing research to identiy the best combinations as well
holds prognostic as well as predictive signicance. Treat- as timing o their use.
ment o patients with MRD-positive disease ater achieve-  In adolescents and young adults, pediatric regimens and
ment o response consists o the use o immunotherapy, the hyper-CVAD regimen showed similar complete remis-
such as blinatumomab or combinatorial agents. sion rates, remission duration, and survival outcomes.
 The rontline therapy o patients with ALL consists o our  The role o allogeneic hematopoietic stem cell transplan-
major components: induction o remission, consolidation, tation (AHSCT) in rst remission remains currently valid
maintenance, and central nervous system prophylaxis. in certain high-risk circumstances, such as (1) KMT2A-
Intensive induction chemotherapy regimens are modeled rearranged ALL, (2) early T-cell precursor ALL, and (3) ALL
ater either the pediatric-inspired roadmap regimens or with complex cytogenetics and hypodiploidy.
the hyper-CVAD (hyperractionated cyclophosphamide,
 In the salvage setting, a number o novel agents have been
vincristine, doxorubicin, and dexamethasone) regimen.
approved, including monoclonal antibodies, bispecic
Consolidation depends on the risk category and consists
antibodies, and chimeric antigen receptor T-cell therapies.
o either consolidation chemotherapy (e.g., high-dose
EPIDEMIOLOGY AND ETIOLOGY 6150 individuals would be diagnosed with ALL in the
United States that year, and 1520 patients would suc-
Acute lymphoblastic leukemia (ALL) is characterized cumb to the disease.1 ALL is projected to represent
by the proliferation and accumulation of lymphoid 20% of adult leukemias and 46% of leukemias in
progenitor cells in the blood, bone marrow, and other teenagers (15–19 years old) and will be the most com-
tissues. It has a bimodal distribution. The overall age- mon childhood acute leukemia in children 14 years old
adjusted incidence is 1.7 per 100,000 persons, with and younger, representing approximately 75% in this
a peak in early childhood and then a smaller peak in patient population.1
older adults. Approximately 60% of cases are diag- The cause of ALL is unknown in most cases.2–6 Chro-
nosed in patients who are 20 years old or younger. mosomal translocations occurring in utero during fetal
In 2020, the American Cancer Society estimated that hematopoiesis have suggested genetic factors as the
3
4 Section I Leukemia
primary cause o pediatric ALL and postnatal genetic WHO classication states that the diagnosis o ALL
events as secondary contributors. Monozygotic and “should be avoided when there are <20% blasts” but
dizygotic twins o patients with ALL and individuals at the same time does recognize that cases o ALL with
with genetic disorders, such as Klineelter (XXY and blasts o less than 20% do exist.9
ChAPTER 1
variants) and Down (trisomy 21) syndromes, or inher- Morphologically, ALL is characterized by the pres-
ited diseases with excessive chromosomal ragility, such ence o a large number o lymphoblasts. Blasts may
as Bloom syndrome, Fanconi anemia, and ataxia telan- show signicant variation in cell size, nuclear shape,
giectasia, have all been ound to have higher incidence visibility o nucleoli, amount o cytoplasm, and cyto-
o ALL, implicating a possible genetic predisposition. plasmic basophilia or vacuolization. Auer rods are
Additional studies have postulated inectious causes.3 consistently absent. In the past, the French-American-
British (FAB) Cooperative Group recommended the
separation o ALL cases into three subtypes (L1, L2,
CLINICAL PRESENTATION AND and L3) based on cytologic characteristics;11 this cyto-
LABORATORY ABNORMALITIES logic classication is no longer used. In act, Burkitt
lymphoma/leukemia, which was a part o B-ALL in
The presenting symptoms can be nonspecic, particu- the FAB classication scheme under the L3 subtype,
larly in children. They largely refect bone marrow has been moved to the mature B-cell lymphoma cat-
ailure and include malaise, atigue, bleeding or bruis- egory.9 Table 1–2 summarizes lineage assignment.
ing, and secondary inections. The B symptoms, such The initial diagnosis o ALL is largely based on fow
as ever, night sweats, and weight loss, are requent. cytometric immunophenotyping (FCI). FCI success-
White blood cell (WBC) count at presentation var- ully assigns lineage in more than 95% o cases. True
ies widely, and circulating blasts are generally noted. mixed-phenotype acute leukemia is rare.12 Aberrant
Symptoms related to hyperleukocytosis are rare in myeloid antigen expression o markers is reported in
ALL, given the lymphoblast morphology, even when 15% to 50% o adult and 5% to 35% o pediatric ALL
WBC counts are high. cases.13–15 ALL blasts are negative or myeloperoxidase
Leukemic involvement o the central nervous sys- (MPO), although a low-level MPO positivity (<3%)
tem (CNS), ranging rom cranial neuropathies to may occur in rare cases that otherwise are typical or
meningeal inltration, occurs in ewer than 10% o ALL.16 The diagnosis o ALL requires the detection o
patients at presentation. It is more common in mature
B-cell acute lymphoblastic leukemia (B-ALL) or Burkitt
Table 1–1 Classifcation o Acute Lympoblastic
leukemia.7 A history or ndings o abdominal masses,
Leukemia
signicant spontaneous tumor lysis syndrome, and
chin numbness (mental nerve) indicating cranial nerve
I. B-lymphoblastic leukemia/lymphoma (B-ALL)
involvement are also more common in this subtype 1. B-ALL, not otherwise specied
o ALL.8 Lymphadenopathy and hepatosplenomegaly, 2. B-ALL with recurrent genetic abnormalities
although rarely symptomatic, are observed in approxi- B-ALL with t(9;22)(q34.1;q11.2); BCR-ABL1
mately 20% o patients.8 B-ALL with t(v;11q23.3); KMT2A rearranged
B-ALL with t(12;21)(p13.2;q22.1); ETV6-RUNX1
B-ALL with hyperdiploidy
DIAGNOSIS B-ALL with hypodiploidy
B-ALL with t(5;14)(q31.1;q32.3); IL3-IGH
The revised World Health Organization (WHO) clas- B-ALL with t(1;19)(q23;p13.3); TCF3-PBX1
sication recognizes three types o ALL: B-ALL, T-cell B-ALL, BCR-ABL1–likea
acute lymphoblastic leukemia (T-ALL), and natural B-ALL with iAMP21a
II. T-lymphoblastic leukemia/lymphoma (T-ALL)
killer cell acute lymphoblastic leukemia (NK-ALL)9
Early T-cell precursor lymphoblastic leukemia (ETP-
(Table 1–1). ALL can involve predominantly bone mar-
ALL)a
row or predominantly extramedullary sites. In patients Near ETP (“close to” ETP) ALLb
with extramedullary lymphoblastic lymphoma, an III. Natural killer (NK) cell lymphoblastic leukemia/
arbitrary cut-o o 25% blasts in bone marrow was lymphomaa
applied to distinguish lymphoblastic leukemia rom
a
Provisional entities in the current World Health Organization (WHO)
lymphoma in the past.10 Currently, this distinction has classication.
been practically abandoned, and the current WHO b
This entity is not recognized in the current WHO classication but is widely
used.
classication uses a combined term “lymphoblastic Data rom Swerdlow SH. WHO Classifcation o Tumours o Haematopoietic and
leukemia/lymphoma.” In contrast to acute myeloid Lymphoid Tissues. International Agency or Research on Cancer; 2017 and Jain
N, Lamb AV, O’Brien S, et al. Early T-cell precursor acute lymphoblastic leukemia/
leukemia, there is no agreed-upon minimal blast per- lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype. Blood.
centage required or a diagnosis o ALL. The current 2016 Apr 14;127(15):1863-1869.
Capter 1 Acute Lymphoblastic Leukemia 5
Table 1–2 Diagnosis o Acute Lympoblastic Leukemia by Immunopenotype
Lineage-Dening Frequent Positive Important Negative

Markers Markers Markers Diagnosis Requirement
ChAPTER 1
B-ALL CD19, CD22, cytoplasmic CD10, HLADR, TDT, CD34 Cytoplasmic CD3, CD19, i strong and uniorm, one
CD79a, cytoplasmic MPO, and monocytic o B markers or CD10; i CD19
IgM,a PAX5 markers weak and partial, two more B
markers or CD10
T-ALL Cytoplasmic CD3 CD7 (bright), variable MPO and monocytic Cytoplasmic CD3 and negative
CD1a, CD2, CD4, CD5, markers;. B-lineage or other lineage markers
CD8, TDT markersa
NK-ALL CD56, CD94, CD161 CD7, CD2, TDT May MPO, and monocytic CD56+, CD94, CD161, TCR gene
express cytoplasmic markers; TCR gene rearrangement germline
CD3b,c rearrangement
a
PAX5 is an excellent B-lineage marker, but it is perormed by immunohistochemistry.
b
May express partial or dim CD19, CD56, or CD79a but oten negative or PAX5. Overall, not sufcient to assign B lineage.
c
Depending on the clone o CD3 with reactivity to cytoplasmic CD3 epsilon chain.
B-ALL, B-cell acute lymphoblastic leukemia; MPO, myeloperoxidase; NK-ALL, natural killer cell acute lymphoblastic leukemia; T-ALL, T-cell acute lymphoblastic leukemia;
TCR, T-cell receptor.
immature markers, such as CD34 or terminal deoxy- ETP-ALL in adolescent and adult patient populations.19
nucleotidyl transerase (TdT), as well as lineage-specic Immunophenotypically, ETP-ALL is dened by the lack
markers. For B-ALL, it requires a combination o strong o CD8 and CD1a, negative or dim expression o CD5
CD19 and at least one additional B-cell marker, such (as dened by CD5 expression in <75% lymphoblasts
as CD22 and cytoplasmic CD79a or CD10; i CD19 is or 1 log scale dimmer than normal T-cells), and expres-
weak, it requires at least two additional markers. Cyto- sion o at least one myeloid or stem cell marker (e.g.,
plasmic CD3 is the lineage-dening marker or T-ALL. CD13, CD33, CD34, CD65, CD117, or HLA-DR).18
In addition, T-ALL is oten bright positive or CD7, Although the original description o ETP-ALL
with variable expression o other markers. CD19 can phenotype stresses the absent or weak CD5 expres-
be aberrantly expressed in 10% to 20% o T-ALL blasts. sion on lymphoblasts, an original study described
The immunophenotypic classication o ALL is three patients with an immunophenotype similar to
summarized in Table 1–2. The original classication ETP except or no decrease in CD5 but showing a
proposed by the European Group or the Immunologi- gene expression prole o ETP-ALL.19 These ndings
cal Characterization o Leukemias in 1995 separated were conrmed in subsequent studies,20 which led to
B-ALL cases into our categories according to the stages the introduction o the term o “near ETP-ALL” (also
o maturation: pro-B-ALL, early pre-B-ALL, pre-B-ALL, known as “close to ETP-ALL”) to describe T-ALL with
and mature B-ALL.17 The mature B-ALL group was a phenotype typical or ETP-ALL with an exception o
subsequently removed rom B-ALL categories. This normal or bright CD5.
immunophenotypic classication o B-ALL is still used NK-ALL has been recently added to the WHO clas-
in some practice, but with the advances in genetic and sication as a provisional entity.9 The entity remains
molecular characterization o B-ALL, its clinical impor- ill-dened and extremely challenging to diagnose,9 in
tance became obsolete. part because o the limited knowledge about early
In contrast to B-ALL, the immunophenotypic clas- stages o NK cell development. The inormation mostly
sication o T-ALL has acquired a critical clinical comes rom ex vivo analyses o normal CD34-positive
importance since the concept o early T-cell precursor progenitor populations;21 the inormation regarding its
lymphoblastic leukemia (ETP-ALL) was introduced.18 malignant counterpart is sparse. The true requency
As with B-ALL, the European Group or the Immu- o NK-ALL remains unknown. The neoplastic cells
nological Characterization o Leukemias separated are reported to express CD56, CD94, and CD161 and
T-ALL cases according to the stages o maturation in cytoplasmic CD3-epsilon. CD2, CD7, and even CD5
our categories: pro-T, pre-T, cortical T, and medullary could be positive, but CD16 is usually absent.9 T-cell
T.17 In 2009, gene expression proling studies in pedi- receptor (TCR) gene rearrangement is germline.
atric patients identied a unique subgroup within the
pro-T category, which was associated with high risk o
induction ailure and relapse and thereater designated
Cytogenetic and Molecular Profling
as ETP-ALL.18 The study conducted at our institution Frequent cytogenetic and molecular abnormali-
conrmed a poor clinical outcome o patients with ties associated with adult ALL oer insight into
leukemogenesis and leukemic progression (Table PTEN mutations are associated with a poor prognosis
1–3).22 They are o both prognostic and predictive sig- in T-ALL.24 Next-generation sequencing (NGS), expres-
nicance and have varying requencies in children and sion proteomics, and oligonucleotide microarrays have
adults, which explains some o the dierences in out- transormed our understanding o the genomic land-
ChAPTER 1
comes in these two groups. This is particularly true in scape o ALL, yielding new molecular subgroups with
the case o B-ALL harboring Philadelphia chromosome actionable targets.25–27
[t(9;22)] (Ph) or other chromosomal changes with prog- Recently, a Ph-like signature has been dened using
nostic relevance, such as t(4;11)/mixed lineage leuke- genome-wide gene expression arrays, which is ound
mia (KMT2A)-AF4. Cytogenetic alterations provide an in 10% o children with standard-risk ALL and as
important basis or B-ALL subclassication. In T-ALL, many as 25% to 30% o young adults with ALL. This
an abnormal karyotype is ound in about 50% to 70% subgroup lacks the expression o BCR-ABL1 usion
o cases, commonly involving TCR loci, 14q11.2/ protein but does have a gene expression prole simi-
TCR alpha/delta, 7p14-15/TCR gamma, or 7q35/TCR lar to BCR-ABL1+ ALL.28–30 The vast majority o these
beta. The partner genes involve 10q24/HOX11,5q35/ patients have deletions in genes encoding key transcrip-
HOX11L2,1q32/TAL1,11p15/LMO1, or 8q24/MYC. tion actors involved in B-cell signaling, such as IKZF1,
del(9p) with the loss o CDKN2A is also common. Acti- TCF3, EBF1, PAX5, and VPREB1, as well as kinase-
vating mutations in NOTCH1 are detected in around activating alterations involving ABL1, ABL2, CRLF2,
50% and FBXW7 in about 30% o cases o T-ALL. CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP,
The presence o NOTCH1/FBXW7 mutations in the or TYK2 and sequence mutations involving FLT3, IL7R,
absence o KRAS/NRAS or PTEN abnormalities is or SH2B3. The most common alterations (~60% in
associated with a good outcome.23 On the other hand, adults) are rearrangements o CRLF2, which activate
the absence o NOTCH1/FBXW7 mutations, the pres- downstream signaling through Janus kinases (JAKs),
ence o KRAS/NRAS mutations, and the presence o and approximately hal o CRLF2-rearranged cases
Table 1–3 Cytogenetic and Molecular Abnormalities in Acute Lympoblastic Leukemia
Category Cytogenetics Involved Genes Adult Frequency (%) Children Frequency (%)
Hyperdiploid 2–15 10–26
Hypodiploid 5–10 5–10
Pseudodiploid t(9;22)(q34;q11) BCR-ABL1 15–25 2–6
del(9)(q21-22) p15, p16 6–30 20
t(4;11);t(9;11); KMT2A 5–10 <5
t(11;19); t(3;11)
del(11)(q22-23) ATM 25–30a 15a
t(12;21)(p12;q22) TEL-AML1 <1b 20–25b
t(1;19) E2A-PBX1 <5 <5
t(17;19) E2A-HLF <5 <5
t(1;14)(p32;q11) TAL1 10–15 5–10
t(7;9)(q34;q32) TAL2 <1 <1
t(10;14)(q24;q11) HOX11 5–10 <5
t(5;14)(q35;q32) HOX11L2 1 2–3
ac
t(1;14)(p32;q11) TCR 20–25 20–25c
del(13)(q14) miR15/miR16 <5 <5
t(8;14); t(8;22); t(2;8) C-MYC 5 2–5
+8 ? 10–12 2
del(7p) ? 5–10 <5
del(5q) ? <2 <2
del(6q); t(6;12) ? 5 <5
a
As determined by loss o heterozygosity.
b
As determined by polymerase chain reaction.
c
In T-cell acute lymphoblastic leukemia, overall incidence <10%.
BCR-ABL1 positive?
Yes No
ChAPTER 1
Positive for CRLF2
STOP by flow cytometry?
Yes
No
FISH for CRLF2 Sending out Run targeted FISH

MDL for JAK2 for kinase based on chromosomal
mutation study fusion testing abnormalities
STOP
FIGURE 1-1 Philadelphia chromosome–like acute lymphoblastic leukemia molecular lesions and associated molecular usions
or mutations. FISH, fuorescence in situ hybridization.
have activating mutations in JAK1 or JAK2 (Fig. 1–1). and the ETV6-NTRK3 usion is sensitive to ALL kinase
CRLF2 expression can be rapidly detected by fow inhibitors (e.g., crizotinib).29 The identication o
cytometry, and a positive CRLF2 expression correlates kinase alterations expands therapeutic options in this
100% with CRLF2 rearrangement by fuorescence in subgroup o ALL with a poor outcome (Table 1–4).
situ hybridization (FISH).31 Importantly, Ph-like ALL At our institution, we use the ollowing algorithm to
with ABL1, ABL2, CSF1R, and PDGFRB expression stratiy B-ALL cases (see Fig. 1–1). For every new patient
usions (the ABL class) has been shown sensitive to with B-ALL, we perorm FISH or BCR/ABL1 and test or
tyrosine kinase inhibitors (TKIs; e.g., dasatinib) both CRLF2 expression by FCI. I FCI detects CRLF2 expres-
by in vitro and in vivo human xenograt models. On sion, FISH studies are ordered to conrm CRLF2 rear-
the other hand, rearrangements in EPOR, IL-7R, and rangement, and molecular studies are ordered to check
JAK2 are sensitive to JAK inhibitors (e.g., ruxolitinib); or JAK2 (or JAK1, JAK3) mutations. In the absence o
Table 1–4 Genetic Determinants in Acute Lympoblastic Leukemia by Lineage
ALL Lineage Cytogenetic Aberration Involved Genes Protein

B-cell BCR/ABL+ (Ph+) IKZF1 Ikaros
CRLF2 + the Ig heavy chain locus or an interstitial PAR1 deletion CRLF2
BCR/ABL-like IKZF1 deletions; rearrangements/mutations in CRLF2, IGH-
CRLF2, and NUP214-ABL1; in-rame usions o EBF1-PDGFRB,
BCR-JAK2, or STRN3-JAK2; cryptic IGH-EPOR rearrangements
Near hypodiploid NRAS, KRAS, FLT3, and NF1
Low hypodiploid IKZF2, and by TP53 disruptions, CDKN2A/B locus deletion
Hyperdiploid CREBBP
NT5C2 mutations NT5C2
TP53 mutations
T-cell PICALM-MLLT10, NUP214-ABL1 usion, EML-ABL1, SET-NUP214
usion, MLL, NOTCH1, FBW7, BCL11B, JAK1, PTPN2, IL7R, PHF6,
RAS/PTEN
ALL, acute lymphoblastic leukemia; Ig, immunoglobulin; mTOR, mammalian target o rapamycin; TKI, tyrosine kinase inhibitor.
BCR/ABL1 rearrangement and CRLF2 expression, the study rom our institution analyzed 215 patients with
sample is sent out or additional molecular testing. newly diagnosed Ph-negative B-ALL who received
intensive chemotherapy and had available MRD
assessment by MFC at CR and around 12 weeks. Early
Measurable Residual Disease
ChAPTER 1
responders dened as MRD negativity at CR had bet-

Measurable residual disease (MRD), or minimal residual ter outcome, with 3-year EFS rates o 65% vs 42% in
disease, is dened as residual leukemic blasts detected late responders (P <.001) and 3-year OS rates o 76% vs
ater cytoreductive chemotherapy despite apparent 58% (P = .001). On multivariate analysis, the KMT2A
morphologic remission (<5% blasts in the bone mar- rearrangement and MRD positivity at CR were the
row). Assessment o MRD has become a standard-o- only actors that correlated with worse OS.40
care practice in the management o patients with ALL
because o its powerul prognostic value as a predic-
tor o relapse and survival.32 The signicant prognostic FRONTLINE ThERAPY
value o MRD spans across all subtypes o ALL and
supersedes that o historical parameters, such as age, The treatment o patients with ALL consists o our
WBC count, and cytogenetics.24 A meta-analysis o major components: induction o remission, consolida-
13,637 pediatric and adult ALL patients showed that tion, maintenance, and CNS prophylaxis.41 The goal o
across all subgroups and covariates, MRD negativity induction is to induce remission by eradicating leukemic
has a hazard ratio (HR) o 0.23 in pediatric patients and cells rom the bone marrow. Intensive induction che-
0.28 in adults or event-ree survival (EFS) and an HR motherapy regimens are modeled ater either the pedi-
o 0.28 in both children and adults or overall survival atric-inspired roadmap regimens or the hyper-CVAD
(OS).33 In adult patients, this translated to 10-year OS (hyperractionated cyclophosphamide, vincristine,
rates o 60% and 15% or patients who were MRD doxorubicin, and dexamethasone) regimen developed
negative and MRD positive, respectively. at MD Anderson Cancer Center (MDACC). Pediatric-
There are dierent methods to assess MRD ater inspired regimens have previously been studied in
treatment, including multiparameter fow cytometry patients o all ages, but their use in patients older than
(MFC), quantitative polymerase chain reaction (PCR), 40 years has largely allen out o avor because o higher
and NGS. Ideally, MRD should be tested on a bone rates o toxicity and treatment-related mortality rates in
marrow sample because it can be 1 to 3 logs higher this patient population, and they are generally reserved
in MRD levels than that in the peripheral blood.34–36 or use in the adolescent and young adult (AYA) popula-
MRD assessment is recommended to perorm on bone tion.42 Ater achieving CR, the consolidation phase aims
marrow with morphologic remission ater induction, to eradicate any residual leukemia cells remaining ater
at approximately 3 months, and every 3 to 6 months induction and, depending on the risk category, consists
thereater. MRD inormation is currently used to guide o either consolidation chemotherapy (e.g., high-dose
postinduction therapy. Bassan et al.37 assigned patients methotrexate and cytarabine) or AHSCT. Consolidation
who achieved complete remission (CR) ater inten- is ollowed by maintenance therapy to prevent relapse
sive chemotherapy to either maintenance or alloge- and prolong remission. Maintenance consists o daily
neic hematopoietic stem cell transplantation (AHSCT) 6-mercaptopurine, weekly methotrexate, and monthly
based on their MRD status and ound a 75% OS rate pulses o vincristine and prednisone or dexamethasone,
or patients who achieved MRD negativity and did not given over 2 to 3 years (POMP [Purinethol, Oncovin,
undergo AHSCT, regardless o their cytogenetic or clin- methotrexate, and prednisone] or DOMP (Dexametha-
ical risk stratication at diagnosis. Another example o sone, Purinethol, Oncovin, and methotrexate), depend-
the use o MRD to guide therapies is the use o blinatu- ing on corticosteroid used).43 Maintenance is omitted
momab in patients with poor MRD clearance. In a mul- in mature B-ALL because o high cure rates, and BCR-
ticenter single-arm phase II study o blinatumomab in ABL1 TKIs are included in all phases or patients with
MRD-positive (≥10-3) B-ALL in morphologic CR, MRD Ph-positive ALL.
negativity was achieved in 88 o 113 (78%) patients. One extensively studied regimen used in treatment
Complete MRD responders had longer relapse-ree sur- o adult ALL is the hyper-CVAD regimen, in which
vival (RFS) (23.6 vs 5.7 months; P = .002) and OS (38.9 vs patients receive hyper-CVAD alternating with high-
12.5 months; P = .002) compared with patients whose dose methotrexate and cytarabine or a total o eight
MRD did not clear ater blinatumomab. The 4-year OS alternating cycles approximately every 3 to 4 weeks.42
rate was 52% among MRD responders.38 These nd- This is ollowed by 2.5 years o POMP maintenance
ings were urther conrmed using propensity score therapy interspersed with intensication courses dur-
matching by comparing them with historical data.39 ing months 6, 7, 18, and 19.
The time to achieve MRD negativity is also a strong The advances made in the eld o immunotherapy
prognostic actor, particularly in Ph-negative ALL. A and the remarkable results achieved in the salvage
setting o ALL led to the investigation o chemoim- cycles, we have changed practice during the metho-
munotherapy in the rontline setting. To improve trexate and cytarabine (even) courses, reversing the
outcomes o younger patients with newly diagnosed sequence o IT therapy to avoid increased risk o neu-
B-ALL, an ongoing phase II trial is investigating the rotoxicity. Thereore, IT cytarabine is administered on
sequential use o hyper-CVAD and blinatumomab day 2 and methotrexate on day 8.48
ChAPTER 1
with promising saety and ecacy. The regimen con- CNS disease is diagnosed by the presence o more
sists o our cycles o hyper-CVAD ollowed by our than ve lymphoblasts per microliter in the cerebro-
cycles o blinatumomab. Blinatumomab is started ater spinal fuid (CSF). Patients with CNS involvement are
two cycles o chemotherapy or patients at high risk treated with triple IT therapy (hydrocortisone 50 mg,
or relapse, including those with Ph-like ALL, complex cytarabine 40 mg, and methotrexate 12 mg) twice per
karyotype, t(4;11), low-hypodiploidy, or near triploidy week until the CSF is negative or malignant cells on
or who are MRD positive. Four cycles o blinatu- two occasions, then weekly IT or our to eight doses
momab are also incorporated in the POMP mainte- ollowed by every other week or our doses, and then
nance (three cycles o POMP ollowed by one cycle o the normal prophylaxis schedule is resumed with the
blinatumomab) or a total o 16 cycles (i.e., 18 months) remaining chemotherapy treatment. Ater this, consol-
o maintenance therapy. Among 27 patients treated, idative craniospinal irradiation is considered in select
the median age was 27 years (range, 18–57 years). The patients with a curative intent, particularly beore
CR rate was 100%, and MRD negativity was achieved AHSCT.
in 96%. There were no induction deaths. One-third o
patients underwent AHSCT because o the presence Philadelphia Chromosome–Positive Acute
o high-risk disease eatures. With a median ollow-up
period o 17 months, 93% o patients were still alive;
Lymphoblastic Leukemia
one patient died ater o AHSCT-related complica- The combination o cytotoxic chemotherapy with
tion, and one died o sepsis during reinduction ater TKIs has been the mainstay o the rontline treatment
relapse. The 1-year RFS and OS rates were 76% and o patients with Ph-positive ALL, with the early intro-
89%, respectively. This trial is currently ongoing at our duction and continuous administration o TKIs lead-
institution (NCT02877303).44 ing to best results.49–52 Imatinib, a rst-generation TKI,
combined with intensive and nonintensive chemo-
Central Nervous System Prophylaxis and therapy, results in CR rates greater than 90% and OS
rates ranging rom 33% to 50%.53,54 The best results
Treatment are achieved when imatinib is administered in a con-
Regularly scheduled lumbar punctures with intrathe- tinuous ashion. Despite the improved outcomes with
cal (IT) chemotherapy are a mainstay o ALL therapy the addition o imatinib to chemotherapy, imatinib
to prevent or treat CNS disease and are implemented resistance is common and leads to a high incidence o
throughout the eight courses o the hyper-CVAD regi- relapse, which led to the evaluation o more potent
men in a risk-adapted manner. In Ph-negative B-ALL TKIs or the rontline treatment o patients with Ph-
and T-ALL, a total o eight IT treatments (two per positive ALL.
course or the rst our courses) are given, which has The second-generation TKI dasatinib has bet-
decreased the rate o isolated CNS relapse to approxi- ter potency and selectivity than the rst-generation
mately 6%.42,45 Because outcomes or patients with TKIs.55 It was rst developed or chronic myeloid
Ph-positive B-ALL improved with the addition o leukemia in patients who could not tolerate or devel-
BCR-ABL TKIs to the hyper-CVAD regimen, leading oped resistance to imatinib. Dasatinib is also reported
to better survival, a higher percentage o CNS relapse to cross the blood–brain barrier.56 A single-institution
is observed with only eight IT courses (~10%).46 The study conducted at MDACC o 72 patients with Ph-
addition o our more IT courses (12 IT in total) in Ph- positive ALL treated with hyper-CVAD and dasatinib
positive B-ALL reduced the CNS relapse rate to 0% in the rontline setting led to 96% CR rate, 83% com-
and hence is our current practice.47 In patients with plete cytogenetic response (CCyR) rate ater the rst
Burkitt leukemia or mature B-ALL, prophylaxis is ur- course, and 65% complete molecular response (CMR)
ther intensied to include 16 IT doses, a dosing strat- rate. The 5-year OS rate was 46%.55 These results
egy that has successully reduced the risk o isolated were conrmed by a multicenter SWOG study o 94
CNS relapse in this patient population.45 patients with newly diagnosed Ph-positive ALL. At a
During hyper-CVAD courses, IT chemotherapy median ollow-up period o 26 months, the CR rate
alternating methotrexate and cytarabine is given on was 88%, and the 3-year OS rate was 71%.57 Dasatinib
days 2 and 8, respectively. However, to avoid the in combination with low-intensity chemotherapy was
simultaneous administration o IT methotrexate and also evaluated. The the European Working Group on
systemic high-dose methotrexate during the even Adult ALL (EWALL) study number 01 or Ph(+) ALL
(EWALL-PH-01) study investigated the combination o days –14 to 29 during course 1). Complete hematologic
dasatinib with low-intensity chemotherapy in patients response occurred in 95% o patients at 6 weeks and
55 years o age or older with newly diagnosed Ph-posi- 91% at 24 weeks. The CMR rate at 24 weeks was 46%.
tive ALL, showing a 96% CR rate, 28% 5-year RFS, and The estimated 24-month OS rate was 60%.64
ChAPTER 1
36% 5-year OS rate.58 The majority (75%) o patients It is worth noting that although none o the TKIs
who relapsed had the T315I mutation, which coners has been compared head to head in Ph-positive ALL,
resistance to all rst- and second-generation TKIs.58 one meta-analysis showed that ponatinib is more
Nilotinib is another second-generation TKI with ecacious than earlier-generation TKIs in the ront-
activity against most imatinib-resistant mutants o line setting, with a higher percentage o patients
ABL1.59 The EWALL international trial investigated achieving CMR with ponatinib-based therapy than
the combination o low-intensity chemotherapy with with earlier-generation TKI-based therapies (79% vs
nilotinib in older adult patients (median age, 65 years) 34%) and a higher OS with ponatinib (2-year, 83%
with Ph-positive ALL. The regimen was well-toler- vs 58%; 3-year, 79% vs 50%),65 and one propensity-
ated. The CR rate was 94%, the 4-year EFS rate was score analysis showed that ponatinib is superior to
42%, and the OS rate was 47%. Thirty-two percent o dasatinib: 3-month CMR rates were 82% versus 65%
patients underwent AHSCT, and the 4-year OS rate or (P = .03); 3-year EFS and OS rates were 69% vs 46%
transplanted patients was 61%.60 (P = .04) and 83% versus 56% (P = .03), respectively.66
Because the emergence o T315I mutation is a driv- The sequential combination o ponatinib combined
ing orce o relapse and the achievement o CMR is with low-intensity chemotherapy ollowed by blina-
associated with better survival, an improvement o tumomab and ponatinib in patients with newly diag-
outcome relies on more potent TKIs that can suppress nosed Ph-positive ALL is currently being investigated
the emergence o T315I mutation. Ponatinib is a third- in a clinical trial (NCT03147612).
generation TKI that is active against the T315I muta- The combination o blinatumomab with TKIs
tion. In a phase II single-arm trial, patients with newly (mainly ponatinib) has been shown to be sae and
diagnosed Ph-positive ALL were treated with ponatinib eective in a small case series o 15 patients rom
and hyper-CVAD.61 Ponatinib was given orally at 45 MDACC with 50% CR rate and 75% CMR rate.67 The
mg/day or the rst 14 days o cycle 1 and then con- GIMEMA group has recently presented early results
tinuously at 45 mg/day or the subsequent cycles. Ater rom D-ALBA, the rst trial investigating the sequen-
treating 37 patients, the protocol was amended ater the tial use o TKIs–steroid (in induction) and blinatu-
occurrence o two atal myocardial events to reduce the momab (in consolidation). Sixty-three patients were
dose o ponatinib to 30 mg/day at cycle 2, with urther treated with this regimen o prednisone, dasatinib, and
reduction to 15 mg when a CMR (dened as absence o blinatumomab. The CR rate was 98%, and the 1-year
quantiable BCR-ABL1 transcripts) was achieved. Ater disease-ree survival (DFS) rate was 88%. Deep molec-
the protocol amendment, no urther vascular events ular response increased throughout therapy (29% ater
occurred. A recent update was reported o 86 patients induction, 60% ater two cycles o blinatumomab,
treated with hyper-CVAD and ponatinib with a median and 80% ater our cycles). Notably, T315I muta-
ollow-up period o 43 months. The 3-month CMR rate tion was noted in 6 o 15 patients with rising MRD
was 74%, and the cumulative CMR rate was 84%. Only in the induction phase, all o which was cleared ater
18 patients (21%) underwent AHSCT in rst CR (CR1). blinatumomab.68 However, T315I resistance muta-
With a median ollow-up period o 44 months, 71% tion and patients harboring IKZF1 and/or PAX5 and/
o patients remain alive in remission, and only three or CDKN2A/B deletions remain a therapeutic chal-
relapses were observed in patients while still taking lenge. Several similar trials are evaluating the combina-
ponatinib. The 5-year CR duration and OS rates were tion o blinatumomab with dasatinib (NCT02143414,
68% and 74%, respectively. A landmark analysis per- NCT04329325) and ponatinib (NCT03263572) in both
ormed at 6 months showed a trend toward better OS rontline and relapsed or reractory settings. At our
in patients who did not undergo AHSCT in rst remis- institution, we are evaluating the combination o pona-
sion (5-year OS rate o 66% or patients who under- tinib with blinatumomab with promising early results.
went AHSCT compared with 83% or patients who
did not [P = .07]).62 The grade 3/4 toxicities included
Philadelphia Chromosome–Like Acute
inections, liver unction test abnormalities, thrombotic
events, myocardial inarction, pancreatitis, and rash.61–63
The Gruppo Italiano Malattie Ematologiche The treatment o patients with Ph-like ALL remains
Ddell’Adulto (GIMEMA) 1811 phase II trial included challenging because o the poor prognosis that this sub-
42 patients with newly diagnosed Ph-positive ALL who type coners. In a retrospective study rom MDACC
were treated with ponatinib at 45 mg/day (or eight con- investigating the outcomes o patients with Ph-like
secutive courses o 6 weeks) and steroids (prednisone ALL treated with standard intensive chemotherapy,
148 patients with untreated Ph-like ALL received 90% to 100%, respectively. O note, the majority o
hyper-CVAD or the pediatric-inspired augmented patients (90%) had low- and intermediate-risk disease:
Berlin-Frankurt-Münster (aBFM) regimen. O the 148 only 13% had marrow involvement, and 3% had CNS
patients, 56 patients (median age, 34 years) had Ph-like involvement, both being known adverse actors.75
ALL, 37 o whom (61%) had CRLF2 overexpression. One concern with the DA-EPOCH-R (dose-adjusted
ChAPTER 1
The majority o patients with CRLF2 rearrangements etoposide phosphate, prednisone, Oncovin, cyclo-
(84%) had concurrent IKZF1 deletion. Patients with Ph- phosphamide, hydroxydaunorubicin, and rituximab)
like ALL had lower rates o MRD negativity at CR and regimen is the lack o highly CNS-penetrating chemo-
a worse 5-year survival rate (23% vs 59%; P = .006).69 therapy agents, such as high-dose methotrexate and
Recently, the outcomes o 24 patients with B-ALL cytarabine, which are essential components o high-
harboring ABL-class usions and treated with a com- intensity chemotherapy or Burkitt leukemia. A recent
bination o TKIs and chemotherapy were reported in report showed signicantly higher 3-year rates o CNS
both rontline (n = 19) and relapse (n = 5) settings. The relapse in patients with Burkitt leukemia treated with
median age was 24 years (range, 5–72 years). Eleven DA-EPOCH compared with regimens that incorporate
patients (46%) harbored IKZF1 deletions. Ater induc- agents with good CNS penetration, such as hyper-
tion therapy, only 16 o 24 patients (67%) achieved CVAD and CODO-M/IVAC (cyclophosphamide, Onc-
CR, all with detectable MRD, including 7 with MRD ovin, doxorubicin, high-dose methotrexate/iosamide,
o 10-2 or greater. In 14 o 18 patients (78%), an MRD etoposide, and high-dose cytarabine) (12% compared
level below 10-4 was achieved within a median time o with 3%–4%), despite the use o IT CNS prophylaxis
2.5 months (range, 1.4–14.8 months) ater TKI initia- with DA-EPOCH.76 A phase III clinical trial comparing
tion. The median remission duration and OS were not R-CODOX-M/R-IVAC (cyclophosphamide, doxorubi-
reached ater a median ollow-up period o 36 months. cin, vincristine, methotrexate/iosamide, etoposide,
The 3-year EFS and OS rates were 55% and 77%, high-dose cytarabine) with DA-EPOCH-R in patients
respectively.70 Given that patients are more likely to with newly diagnosed high risk mature B-ALL is
remain MRD positive ater induction therapy, the use underway (EudraCT Number: 2013-004394-27).
o blinatumomab as rontline or or MRD in CR1 may
improve outcomes.
CD20-Positive Precursor B-Cell Acute
Our current treatment strategies in patients with
Ph-like ALL include the use o TKIs in patients with
ABL-class usions and blinatumomab and inotuzumab Expression o cell surace marker CD20 in adult ALL
ozogamicin combinations mainly among patients with ranges rom 35% to ubiquitous, depending on the
CRLF2 and JAK activations. subtype, and has been associated with an inerior
prognosis.77 The addition o two doses o monoclo-
Mature B-Cell and Burkitt Acute nal CD20 antibody (rituximab) administered with the
rst our cycles o chemotherapy and during mainte-
Lymphoblastic Leukemia nance intensication at months 6 and 18 resulted in
The addition o rituximab to short intensive che- improved OS in younger patients compared with simi-
motherapy has improved outcomes in adults with lar chemotherapy historical control participants (75%
Burkitt and Burkitt-type lymphoma or ALL. 71–73 Its vs 47% at 3 years; P = .003).45 Similar results were
addition to hyper-CVAD resulted in a 3-year survival reported by the German Multicenter Study Group or
rate o 89% compared with 53% with chemotherapy ALL (GMALL).78 The addition o rituximab to che-
alone. This was conrmed in a randomized, open- motherapy in the GRAAL-R 2005 randomized study
label, phase III trial, in which 260 patients with newly improved the 2-year EFS and OS rates rom 52% to
diagnosed Burkitt lymphoma/leukemia received 65% (P = .038) and 64% to 71% (P = .095; censoring
intensive chemotherapy with or without rituximab. or AHSCT, P = .018), respectively.79
The addition o rituximab improved EFS (3-year rate, Oatumumab is a second-generation anti-CD20
75% vs 62%; P = .024) and OS (3-year rate, 83% vs monoclonal antibody that has a dierent binding site
70%; P =.011).74 than rituximab, targeting a membrane proximal small-
To urther reduce early morbidity and mortality, a loop epitope on the CD20 molecule.80 Oatumumab in
pilot study investigated dose-adjusted EPOCH (eto- combination with hyper-CVAD was ound to be highly
poside phosphate, prednisone, Oncovin, cyclophos- eective in a phase II study o 69 patients with newly
phamide, and hydroxydaunorubicin) in combination diagnosed Ph-negative CD20-positive B-ALL. All but
with rituximab in 30 patients (median age, 33 years; one patient (98%) achieved CR, and the MRD negativ-
age older than 40 years, 40%) diagnosed with Burkitt ity rate was 93% overall. At a median ollow-up period
lymphoma. The treatment was sae and highly eec- o 44 months, the median RFS was 52 months, and the
tive. The PFS and OS rates were 95% to 100% and median OS was not reached. The 4-year RFS and OS
rates were 60% and 68%, respectively. For AYAs, the tailoring ALL therapy to the dierent treated popu-
4-year OS rate was 74%. Overall, the combination o lations. Such dierences include (1) a higher T-cell
hyper-CVAD plus oatumumab was highly eective. phenotype in patients aged 10 to 40 years old; (2) a
Oatumumab is our preerred anti-CD20 monoclonal near absence o the two avorable subgroups o ALL
ChAPTER 1
antibody in ALL, particularly or patients with CD20 (hyperdiploidy and t(12;21)/ETV6-RUNX1) during the
expression less than 20%.81 second decade o lie compared with a 60% preva-
lence in children; and (3) an increasing prevalence o
T-Cell Acute Lymphoblastic Leukemia high-risk Ph-positive ALL with age, rom 3% in chil-
dren to almost 50% in older adults.89 In the US inter-
Treatment o adults with T-ALL and T-cell lympho- group trial C10403 o 295 AYA patients (17–39 years
blastic lymphoma (T-LL) results in long-term survival o age) treated with a pediatric regimen, the 3-year
rates o 40% to 60%; the outcome is strongly asso- OS rate was 73%.90 At MDACC, a nonrandomized
ciated with the T-cell phenotype.18,82 Nelarabine, a study including AYA patients showed no dierence
T-cell-specic purine nucleoside analog, is approved or between the pediatric asparaginase-containing aBFM
the treatment o patients with relapsed and reractory regimen and the non-asparaginase-containing hyper-
T-ALL, leading to CR rates o 31% to 36% in phase II CVAD regimen. The 5-year CR duration rate was 53%
trials,83,84 allowing some patients to undergo AHSCT with hyper-CVAD, compared with 55% with aBFM.
with long-term survival. In the pediatric experience, The 5-year OS rates were 60% in both groups. The
the addition o nelarabine to rontline aBFM chemo- aBFM regimen had a higher incidence o asparaginase
therapy in patients with T-ALL up to 31 years o age adverse eects, such as hepatotoxicity (41%), pancre-
improved the 4-year DFS rate rom 83% with aBFM atitis (11%), and thrombosis (19%), and myelosup-
alone to 89% (P = .0332).85 However, these results have pression-related complications were more common
not yet been replicated in adult patients. A single-arm with hyper-CVAD.91 More recently, the hyper-CVAD
phase II study rom MDACC o nelarabine combined and oatumumab combination reported a 4-year OS
with rontline hyper-CVAD regimen in 67 patients rate o 74% in the AYA population.81
ailed to improve CR duration or OS rates compared In summary, pediatric regimens and the hyper-
with historical control participants treated with hyper- CVAD regimen showed similar CR, remission duration,
CVAD alone.86 This study has now been amended to and survival outcomes. In the absence o a randomized
include the incorporation o nelarabine, peg-asparagi- study comparing both regimens in the AYA popula-
nase, and venetoclax into the hyper-CVAD regimen. tion, our practice is to use the hyper-CVAD regimen
Recent insights into the biology o ETP-ALL have as a backbone or clinical trial development because
revealed BCL-2 dependence, which perhaps explains this regimen has less organ-specic toxicity than aspar-
the sensitivity to BCL-2 antagonism.87 The addition o aginase-based regimens and is thus more conducive to
venetoclax to lower-intensity chemotherapy in older combination with investigational agents.
adults with newly diagnosed ALL has yielded encourag-
ing early results in interim reports o 10 patients treated
(three with T-ALL, including two with ETP-ALL), with
Acute Lymphoblastic Leukemia in Older
90% CR/CR with incomplete hematologic recovery
Patients
(CRi) rate and 90% MRD negativity.88 The combination In older patients with ALL (generally dened as those
o venetoclax and navitoclax may also be particularly older than 55–60 years), intensive chemotherapy
promising in this subgroup. Clinical trials evaluating results in CR rates o 80% but with unacceptable
the ecacy and saety o venetoclax with navitoclax toxicities.92 One-third o patients achieving CR may
(NCT03181126) and in combination with chemother- die o myelosuppression-associated complications.
apy (NCT03808610; NCT03504644; NCT03576547; The historical long-term cure rate is 15% to 20%.93
NCT03319901) in patients with relapsed and rerac- Among 727 older adult patients (older than 65 years;
tory ALL are currently ongoing. Studies evaluating the 2007–2012) treated under Medicare, the majority o
biology o near ETP-ALL are ongoing at our institution patients did not receive chemotherapy; in those who
to better tailor the treatment and thus improve the out- received chemotherapy, the median OS period was
come o this poor-risk subgroup. only 10 months.94 In the National Cancer Institute
Surveillance, Epidemiology, and End Results database,
Adolescent and Young Adult Acute among 1675 adults (age 60 years or older) with ALL
(1980–2011), the median survival time was 4 months,
Lymphoblastic Leukemia and the 3-year survival rate was 12.8%.95
The AYA population consists o patients 15 to 39 years Strategies to de-intensiy treatment regimens have
o age. The biology o ALL diers between children, been thus investigated in this population. Inotuzumab
AYAs, and older adults, which is the rationale behind ozogamicin with mini hyper-CVD (i.e., a lower
Another random document with
no related content on Scribd:
attempt elsewhere in a circuit of a few [268]inches. No exploration of
the gallery—no anxiety for the distressed larva; though the grub,
whose delicate skin has just exchanged the gentle moisture of a
cave for burning sunshine, is writhing on its heap of chewed Diptera,
the mother takes no notice of it. For her it is no more than any one of
the objects strewn on the sand,—a little pebble, a clod, a scrap of
dried mud,—nothing more. It is undeserving of attention. This tender,
faithful mother, who wears herself out in efforts to reach her
nursling’s cradle, cares nothing just now but for her entrance door—
the door she is used to. That which goes to her maternal heart is the
longing to find the well-known passage. Yet the way is open; nothing
holds her back, and under her eyes wriggles the grub, the final
object of her anxiety. With one spring she would be at the side of the
unhappy larva who so needs help. Why does she not rush to her
beloved nursling? She could dig a new habitation and get it swiftly
underground. But no—she persists in seeking a way which no longer
exists, while her son is grilled under her eyes. I was boundlessly
surprised by this obtuse maternity, since maternity is the most
powerful and most fertile in resource of all feelings which move the
animal. Hardly could I have believed my eyes but for endless
experiments on the Cerceris and Philanthidæ, as well as on
Bembecidæ of different species. Stranger still, the mother, after long
hesitation, at length entered the unroofed passage—all that was left
of the corridor. She advanced, drew back, and gave a few careless
sweeps without stopping. Guided by vague recollections, and
perhaps by the smell of [269]venison exhaled from the heap of
Diptera, she came occasionally as far as the end of the gallery, the
very spot where lay the larva. Mother and son had met. At this
moment of reunion after long anxiety, were there earnest solicitude,
sign of tenderness, or of maternal joy? Whoever thinks so has only
to repeat my experiment to convince himself of the contrary. The
Bembex did not recognise her larva at all; it was a worthless thing, in
her way,—nothing but an embarrassment. She walked over it and
trampled it unheeding, as she hurried backwards and forwards. If
she wanted to dig at the bottom of the cell, she rudely kicked it
behind her,—pushed, upset, expelled it, as she might have treated a
large bit of gravel which got in her way while at work. Thus
maltreated, the larva bethought itself of defence. I have seen it seize
her by one tarsus with no more ceremony than she would have
shown in biting the foot of a Dipteron caught by her. The struggle
was sharp, but at last the fierce mandibles let go, and the mother
flew wildly away with her sharpest hum. This unnatural scene of the
son biting the mother, and perhaps even trying to eat her, is unusual,
and brought about by circumstances which the observer is not
always able to conjure up. What one can always witness is the
profound indifference of the Hymenopteron for its offspring, and the
brutal disdain with which that inconvenient heap, the grub, is treated.
Once she has raked out the far end of the passage, which is done in
a moment, the Bembex returns to her favourite point, the threshold,
to resume her useless researches. As for the grub, it continues to
struggle [270]and wriggle wherever the maternal kicks may have
landed it. It will perish unaided by its mother, who could not
recognise it because she was unable to find the passage she was
used to. If we return to-morrow, we shall find it in the gallery, half-
broiled by the sun, and already a prey to the flies—once its own
prey.
Such is the connection in acts of instinct; one leading to the next in

an order that the most serious circumstances have no power to alter.
After all, what was the Bembex seeking? Her larva, evidently. But to
reach this larva she had to enter the burrow, and to enter the burrow
she had to find the door, and the mother persists in seeking this door
while the gallery lay open with provender and larva all before her.
The ruined abode, the endangered family, were for the moment
unimportant; all she could think of was the familiar passage reached
through loose sand. Let all go—habitation and inhabitant—if this
passage be not found! Her actions are like a series of echoes,
awaking one another in a fixed order, the following one only
sounding when the preceding has sounded. Not because there was
any obstacle; the burrow was all open, but for want of the usual
entrance the first action could not take place. That decides
everything; the first echo is mute, and so all the rest are silent. What
a gulf between intelligence and instinct! Through the ruins of the
shattered dwelling a mother guided by intelligence rushes straight to
her son; guided by instinct she stops obstinately where once was the
door. [271]
[Contents]
XX
MASON BEES
Réaumur has dedicated one of his studies to the Chalicodoma of walls, which
he calls the Mason Bee. I propose to resume this study, to complete it, and
especially to consider it from a point of view entirely neglected by that illustrious
observer. And first of all I am tempted to state how I made acquaintance with this
Hymenopteron. It was when I first began to teach—towards a.d. 1843. On
leaving the Normal School of Vaucluse a few months previously, with my
certificate, and the naïve enthusiasm of eighteen, I was sent to Carpentras to
manage the primary school belonging to the college. A singular school it was,
upon my word, notwithstanding its fine title of “Upper”!—a kind of vast cellar
breathing out the damp engendered by a fountain backing on it in the street.
Light came in through a door opening outward when the weather allowed of it,
and a narrow prison-window, with iron-bars, and little diamond panes set in lead.
For seats there was a plank fastened to the walls all round the room; in the
middle was a chair guiltless of straw, a blackboard, and a bit of chalk. [272]
Morning and evening, at the sound of a bell, there tumbled in some fifty young
rascals, who, having failed to master De viris and the Epitome, were devoting
themselves, as one said then, to “some good years of French.” The failures at
“Rosa, a Rose,” came to me to learn a little spelling. Children were mingled with
tall lads at various stages of education, and all distressingly agreed in playing
tricks on the master—no older, even younger, than some of themselves.
I taught the little ones to read syllables, the middle ones to hold a pen in the right
way while writing a few words of dictation on their knees; for the eldest I unveiled
the secrets of fractions, and even the mysteries of the hypotenuse. And the only
means I had to keep this restless crowd in order, give each mind appropriate
food, arouse attention, expel dulness from the gloomy room whose very walls
dripped melancholy, were my tongue and a bit of chalk.
For that matter there was equal disdain in the other classes for all which was not
Latin or Greek. One instance will suffice to show the style in which physical
science was treated, now so large a part of education. The principal of this
college was an excellent man—the worthy Abbé X, who, not anxious himself to
grow green peas and bacon, turned over such matters to some relation of his,
and undertook to teach physical science.
[To face p. 272.
MASON BEES—CHALICODOMA MURARIA ON OLD NEST
Let us attend one of his lessons, which happens to be on the barometer. By

good luck the college owned one. It was an old article, very dusty, hung high out
of reach of profane hands, and bearing on [273]its face in large letters the words,
Storm, Rain, Fine. “The barometer,” began the good abbé, addressing himself to
his disciples—he used a fatherly second person singular to each,—“the
barometer gives notice of good or bad weather. Thou seest the words written
here—Storm, Rain—thou seest, Bastien?” “I see,” replies Bastien, the most
mischievous of the troop. He has run through his book, and knows more about
the barometer than does his professor. “It is composed,” the abbé goes on, “of a
curved glass tube full of mercury which rises and falls according to the weather.
The small branch of this tube is open; the other—the other—we shall see as to
the other. Bastien—Get on this chair, and just feel with the tip of thy finger if the
long branch is open or closed. I do not quite remember.” Bastien goes to the
chair, stands as high as he can on tip-toe, and feels the top of the long column
with a finger tip. Then, with a slight smile under the down of his dawning
moustache, he replies, “Yes, exactly; yes, the long branch is open at the top. I
can feel the hollow.” And to corroborate his mendacious statement he went on
moving his forefinger on the top of the tube, while his co-disciples, accomplices
in mischief, stifled their laughter as best they could. The abbé said calmly, “That
will do. Come down, Bastien. Gentlemen, write in your notes that the long
branch of the barometer is open. You might forget it. I had forgotten it myself.”
Thus were physics taught. Things mended, however; a master came, and came
to stay,—one who knew that the long branch of a barometer is [274]closed. I
obtained tables on which my pupils could write instead of scrawling on their
knees, and as my class grew daily larger, it ended by being divided. As soon as I
had an assistant to look after the younger ones, things changed for the better.
Among the subjects taught, one pleased master and pupils equally. This was
out-of-door geometry, practical surveying. The college had none of the
necessary outfit, but with my large emoluments—700 francs, if you please!—I
could not hesitate as to making the outlay. A measuring chain and stakes, a
level, square, and compass were bought at my expense. A tiny graphometer,
hardly bigger than one’s palm, and worth about 4s. 2d., was furnished by the
college. We had no tripod, and I had one made. In short, my outfit was complete.
When May came, once a week the gloomy class-room was exchanged for the
fields, and we all felt it as a holiday. There were disputes as to the honour of
carrying the stakes, divided into packets of three, and more than one shoulder
as we went through the town felt glorified in the sight of all by the learned
burden. I myself—why conceal it?—was not without a certain satisfaction at
carrying tenderly the most precious part of the apparatus, the famous four-and-
twopenny graphometer. The scene of operations was an uncultivated pebbly
plain—a harmas, as we call it in these parts. No curtain of live hedge, no
bushes, hindered me from keeping an eye upon my followers; here—an all
important condition—I need not fear temptation from green apricots for my
scholars. There was free scope for all imaginable [275]polygons; trapezes and
triangles might be joined at will. Wide distances suggested plenty of elbow room,
and there was even an ancient building, once a dovecote, which lent its vertical
lines to the service of the graphometer.
Now from the very first a suspicious something caught my attention. If a scholar
were sent to plant a distant stake I saw him frequently pause, stoop, rise, seek
about, and stoop again, forgetful of straight line and of signals. Another, whose
work it was to pick up pegs, forgot the iron spike and took a pebble instead; and
a third, deaf to the measurements of the angle, crumbled up a clod. The greater
number were caught licking a bit of straw, and polygons stood still, and
diagonals came to grief. What could be the mystery? I inquired, and all was
explained. Searcher and observer born, the scholar was well aware of what the
master was ignorant of—namely, that a great black bee makes earthen nests on
the pebbles of the harmas, and that in these nests there is honey. My surveyors
were opening and emptying the cells with a straw. I was instructed in the proper
method. The honey, though somewhat strong-flavoured, is very acceptable; I in
turn acquired a taste for it, and joined the nest-hunters. Later, the polygon was
resumed. Thus it was that for the first time I saw Réaumur’s Mason Bee,
knowing neither its history nor its historian.
This splendid Hymenopteron, with its dark violet wings and costume of black
velvet, its rustic constructions on the sun-warmed pebbles among the thyme, its
honey, which brought diversion from the severities [276]of compass and square,
made a strong impression on my mind, and I wished to know more about it than
my pupils had taught me—namely, how to rob the cells of their honey with a
straw. Just then my bookseller had for sale a magnificent work on insects, The
Natural History of Articulated Animals, by de Castelnau, E. Blanchard, and
Lucas. It was enriched with many engravings which caught the eye. But alas, it
had a price—such a price! What did that matter? My 700 francs ought surely to
suffice for everything—food for the mind as well as for the body. That which I
bestowed on the one I retrenched from the other—a balance of accounts to
which whoever takes science for a livelihood must needs resign himself. The
purchase was made. That day I bled my university stipend abundantly; I paid
away a whole month of it. It took a miracle of parsimony to fill up the enormous
deficit.
The book was devoured—I can use no other word. There I learned the name of
my black bee, and there I read for the first time details of the habits of insects,
and found, with what seemed to my eyes an aureole round them, the venerated
names of Réaumur, Huber, Léon Dufour; and while I turned the pages for the
hundredth time, a voice whispered vaguely, “Thou too shalt be a historian of
animals!” Naïve illusions! where are you? But let us banish these recollections,
both sweet and sad, and come to the doings of our black bee.
Chalicodoma, house of pebbles, rough-cast mortar, a name which would be

perfect did it not look odd to any one not well up in Greek. It is a [277]name
applied to those Hymenoptera that build cells with materials such as we use for
our dwellings. It is masonry, but made by a rustic workman, better used to dried
clay than to hewn stone. A stranger to scientific classification (and this causes
great obscurity in some of his memoirs), Réaumur called the worker after the
work, and named our builders in dried clay Mason Bees, which paints them
exactly. We have two kinds, C. muraria, whose history is admirably given by
Réaumur, and C. sicula, which is not special to the land of Etna, as the name
suggests, but is found in Greece, Algeria, and the Mediterranean region of
France, especially in the department of Vaucluse, where in May it is one of the
most common Hymenoptera. The two sexes of C. muraria are so unlike in
colouring that a novice observing both coming out of the same nest would take
them for strangers to one another. The female is of a splendid velvet black, with
dark violet wings; in the male the black velvet is replaced by a bright iron-red
fleece. The second species—a much smaller one—has not this difference of
colour, both sexes wearing the same costume—a general mixture of brown, red,
and ashy tints. Both begin to build in the beginning of May. The wing-tips,
washed with violet on a bronze ground, faintly recall the rich purple of the first
species.
As Réaumur tells us, C. muraria in the northern provinces chooses as the place
to fix her nest a wall well exposed to the sun and not plastered, as the plaster
might come off and endanger her cells. She only entrusts her constructions to a
solid foundation, such as a bare stone. I see that she is equally [278]prudent in
the south, but, for some reason unknown to me, she generally chooses some
other base than the stone of a wall. A rolled pebble, often hardly larger than
one’s fist,—one of those with which the waters of the glacial period covered the
terraces of the Rhône valley,—is her favourite support. The great ease with
which such a one is found may influence her; all our slightly raised plateaux, all
our arid thyme-clad ground, are but heaped pebbles cemented with red earth. In
the valleys the bee can also use the stones gathered in torrent beds; near
Orange, for instance, her favourite spots are the alluviums of the Aygues, with
their stretches of rolled boulders no longer visited by water. Or if a pebble be
wanting, she will establish her nest on a boundary stone or an enclosing wall.
Chalicodoma sicula has a yet greater variety of choice. Her favourite position is
under a tile projecting from the edge of a roof. There is scarcely a little dwelling
in the fields that does not thus shelter her nests. There, every spring, she
establishes populous colonies, whose masonry, transmitted from one generation
to another, and yearly enlarged, finally covers a very considerable surface. I
have seen such a one under the tiles of a shed, which spread over five or six
square yards. When the colony were hard at work, their number and humming
fairly made one dizzy. The underpart of a balcony pleases them equally, or the
frame of an unused window,—above all, if closed by a sun-shutter, which offers
a free passage. But these are great meeting-places, where labour, each for
herself, hundreds and thousands of workers. If alone, which not seldom occurs,
Chalicodoma [279]sicula establishes herself in the first little spot she can find, so
long as it has a solid basis and heat. As for the nature of this basis it matters
little. I have seen nests built on bare stones and brick, on a shutter, and even on
the glass panes in a shed. One thing only does not suit the bee—namely, the
stucco of our houses. Prudent, like her retainer C. muraria, she would fear ruin
to her cells did she entrust them to a support which might fall.
Finally, for reasons which I cannot yet satisfactorily explain, C. sicula often
entirely changes her manner of building, turning her heavy mortar dwelling,
which seems to require a rock to support it, into an aerial one, hung to a bough.
A bush in a hedge,—no matter what—hawthorn, pomegranate, or Paliurus,—
offers a support, usually about the height of a man, Ilex and elm give a greater
height. The bee chooses in some thicket a bough about as thick as a straw, and
constructs her edifice on this narrow base with the same mortar which would be
used under a balcony or the projecting edge of a roof. When finished, the nest is
a ball of earth, traversed literally by the bough. If made by a single insect it is the
size of an apricot, and of a fist if several have worked at it; but this seldom
occurs.
Both species use the same materials, a calcareous clay, mixed with a little sand
and kneaded with the mason’s own saliva. Damp spots which would facilitate
labour and spare saliva to mix mortar are disdained by the Chalicodoma, which
refuses fresh earth for building, just as our builders refuse old plaster and lime.
Such materials when soaked with humidity would not hold properly. What is
needed is a dry [280]powder, which readily absorbs the disgorged saliva, and
forms with the albuminous principles of this liquid a kind of Roman cement,
hardening quickly,—something like what we obtain with quicklime and white of
egg.
[To face p. 280.
MASON BEES—CHALICODOMA SICULA AND NEST
A beaten road, formed of calcareous boulders crushed by passing wheels into a

smooth surface like paving stones, is the quarry whence Chalicodoma sicula
prefers to get mortar; whether she builds on a branch, in a hedge, or under the
jutting roof of some rural habitation, it is always from a neighbouring path, or a
road, or the highway, that she seeks materials—indifferent to the constant
passing of beasts and travellers. You should see the active bee at work when
the road is dazzling white in the hot sunshine. Between the neighbouring farm
where she is building and the road where the mortar is prepared, there is the
deep hum of the bees perpetually crossing each other as they come and go.
The air seems traversed by constant trails of smoke, so rapid and direct is their
flight. Those who go carry away a pellet of mortar as big as small shot; those
who come settle on the hardest and driest spots. Their whole body vibrates as
they scratch with the tips of their mandibles, and rake with their forefeet to
extract atoms of earth and grains of sand, which, being rolled between their
teeth, become moist with saliva and unite. They work with such ardour that they
will let themselves be crushed under the foot of a passer-by rather than move.
Chalicodoma muraria, however, which seeks solitude, far from human
habitation, is rarely seen on beaten paths; perhaps they are too distant from the
places where she builds. If [281]she can find dry earth, rich in small gravel, near
the boulder chosen as the basis of her nest, she is contented. She may either
make quite a new nest in a spot hitherto unoccupied, or over the cells of an old
one, after repairing them. Let us consider the first case.
After choosing a boulder, she comes with a pellet of mortar in her mandibles,
and arranges it in a ring on the surface of the pebble. The forefeet, and above all
the mandibles, which are her most important tools, work the material, which is
kept plastic by the gradually disgorged saliva. To consolidate the unbaked clay,
angular pieces of gravel, as large as a small bean, are worked in singly on the
outside of the still soft mass. This is the foundation of the edifice. Other layers
are added until the cell has the required height of three or four centimetres. The
masonry is formed by stones laid on one another and cemented with lime, and
can stand comparison with our own. True, to economise labour and mortar, the
bee uses coarse materials,—large bits of gravel, which in her case answer to
hewn blocks. They are chosen singly—very hard ones, almost always with
angles which, fitted together, give mutual support, and add solidity to the whole.
Layers of mortar, sparingly used, hold them together. The outside of the cell thus
assumes the look of a piece of rustic architecture, in which stones project with
their natural inequalities; but over the inside, which requires a smoother surface
in order not to wound the tender skin of the larva, is spread a wash of pure
mortar—artlessly, however, as if by broad sweeps of a trowel; and when it has
eaten up its honey paste, the grub [282]takes care to make a cocoon and hang
the rude wall of its abode with silk. The Anthophora and Halictus, whose larvæ
spin no cocoon, varnish the inside of their earthen cells delicately, giving them
the polish of worked ivory.
The construction, the axis of which is always nearly vertical, with an orifice
opening upward, so that the fluid honey may not run out, differs a little in form,
according to its basis. On a horizontal surface it rises like a little oval tower; on a
vertical or slanting one it resembles half a thimble cut down its length. In this
case the support—the pebble itself—completes the surrounding wall. The cell
completed, the bee sets to work at once to store it. The neighbouring flowers,
especially those of Genista scorpius, which in May turn the alluviums of the
torrents golden, furnish sugared liquid and pollen. She comes with her crop
swelled with honey, and all yellow underneath with pollen dust, and plunges
head first into the cell, where for some moments one may see her work her body
in a way which tells that she is disgorging honey. Her crop emptied, she comes
out, but only to go in again at once—this time backwards. With her two hind feet
she now frees herself from her load, of pollen by brushing herself underneath.
Again she goes out, and returns head first. She must stir the materials with her
mandibles for a spoon, and mix all thoroughly together. This labour of mixing is
not repeated after every journey, but only from time to time, when a considerable
quantity has been collected. When the cell is half full, it is stored; an egg must
be laid on the honey paste, and the door [283]has to be closed. This is all done
without delay. The orifice is closed by a cover of undiluted mortar, worked from
the circumference to the centre. Two days at most seem required for the whole
work, unless bad weather or a cloudy day should interrupt it. Then, backing on
the first cell, a second is built and stored in the same way, and a third and fourth,
etc., follow, each one with honey and an egg, and closed before another is
begun. Work once begun is continued until it is completed, the bee never
building a new cell until the four acts required to perfect the preceding one are
performed—namely, construction, provisioning, an egg, and sealing the cell.
As Chalicodoma muraria always works alone on her chosen boulder, and shows
great jealousy if her neighbours alight there, the number of cells clustered on
one pebble is not great—usually six to ten. Are some eight larvæ her whole
progeny, or will she establish a more numerous family on other boulders? The
surface of the stone would allow of more cells if she had eggs for them, and the
bee might build there very comfortably without hunting for another, or leaving the
one to which she is attached by habit and long acquaintance. I think, therefore,
that most probably all her scanty family are settled on the same stone—at all
events when she builds a new abode.
The six or ten cells composing the group are certainly a solid dwelling, with their
rustic covering of gravel, but the thickness of their walls and lids—two
millimetres at most—hardly seems sufficient against rough weather. Set on its
stone in the open [284]air, quite unsheltered, the nest will undergo the heat of
summer suns which will turn every cell into an oven; then will come the autumn
rains which will slowly eat away the masonry, and then winter frosts which will
crumble what the rain may have respected. However hard the cement may be,
can it resist all these attacks, and if it can, will not the larvæ, sheltered by so thin
a wall, suffer from over-heat in summer and too keen cold in winter?
Without having gone through all these arguments, the bee acts wisely. When all
the cells are completed she builds a thick cover over the whole group, which,
being of a material impermeable to water and almost a non-conductor, is at once
a defence against heat and cold and damp. This material is the usual mortar,
made of earth and saliva, only with no small stones in it. The bee lays it on,—
one pellet after another, one trowelful and then a second,—till there is a layer a
centimetre thick over all the cells, which disappear entirely under it. The nest is
now a rude dome, about as big as half an orange; one would take it for a clod of
mud, half crushed by being flung against a stone where it had dried. Nothing
outside betrays its contents—no suggestion of cells—none of labour. To the
ordinary eye it is only a chance splash of mud.
This general cover dries as rapidly as do our hydraulic cements, and the nest is
almost as hard as a stone. A knife with a strong blade is needed to cut it. In its
final shape the nest recalls in no degree the original work; one would suppose
the elegant turrets adorned with pebble work, and the final dome, looking like a
bit of mud, to be the work of [285]two different species. But scratch away the
cover of cement and we recognise the cells and their layers of tiny pebbles.
Instead of building on a boulder yet unoccupied, Chalicodoma muraria likes to
utilise old nests which have lasted through the year without notable injury. The
mortared dome has remained much as it was at the beginning, so solid was the
masonry; only it is pierced by a number of round holes corresponding to the
chambers inhabited by the larvæ of the past generation. Such dwellings, only
needing a little repair to put them in good condition, economise much time and
toil; so Mason Bees seek them, and only undertake new constructions when old
nests fail them.
From the same dome come forth brothers and sisters—reddish males and black
females—all descendants of the same bee. The males lead a careless life,
avoiding all labour, and only returning to their clay dwellings for a brief courtship
of their ladies; and they care nothing for the deserted dwelling. What they want
is nectar from flower-cups, not mortar between their mandibles. But there are the
young mothers, who have sole charge of the future of the family—to which of
them will fall the inheritance of the old nest? As sisters they have an equal right
to it—so would human justice decide, now that it has made the enormous
progress of freeing itself from the old savage right of primogeniture; but Mason
Bees have not got beyond the primitive basis of property—the right of the first
comer.
So when the time to lay has come, a bee takes the first free nest which suits her
and establishes herself [286]there, and woe to any sister or neighbour who
thenceforward disputes possession of it. A hot reception and fierce pursuit would
soon put the new-comer to flight; only one cell is wanted at the moment out of all
which gape like little wells around the dome, but the bee calculates that by and
by the rest will be useful, and she keeps a jealous watch on them all and drives
away every visitor. I cannot remember having seen two Mason Bees working on
the same pebble.
The work is now very simple. The bee examines the inside of the old cell to see
where repairs are needed, tears down the rags of cocoon hanging on the walls,
carries out the bits of earth fallen from the vault pierced by the inhabitant in
order to get out, mortars any places out of repair, mends the orifice a little, and
that is all. Then comes storage, laying an egg, and stopping up the cell. When
these are successively completed, the general cover, the mortar dome, is
repaired if necessary, and all is finished.
Chalicodoma sicula prefers a sociable life to a solitary one, and hundreds—nay,

several thousands—will establish themselves on the under surface of the tiles
on a hovel, or the edge of a roof. It is not a real society with common interests,
dear to all, but merely a gathering where each works for herself and is not
concerned for the rest—a throng recalling the swarm of a hive only by their
number and industry. They use the same mortar as Chalicodoma muraria,
equally resistant and waterproof, but finer and without pebbles. First the old
nests are utilised. Every free cell is repaired, stored, and shut up. But the old
ones are far from sufficing to the population, which increases rapidly year by
year, and on the [287]surface of the nest, where the cells are hidden below the
old general mortar covering, new ones are built as required. They are placed
more or less horizontally, one beside another, with no kind of order. Every
constructor builds as the fancy takes her, where and as she wills; only she must
not interfere with her neighbour’s work, or rough treatment will soon call her to
order. The cells accumulate in chance fashion in this workyard, where there is
no general plan whatever. Their form is that of a thimble divided down the axis,
and their enclosure is completed either by adjacent cells, or the surface of the
old nest. Outside they are rough, and look like layers of knotted cords
corresponding to the layers of mortar. Inside the walls are level but not smooth;
a cocoon will replace the absent polish.
As soon as a cell is built it is stored and walled up, as we have seen with
Chalicodoma muraria. This work goes on through the whole of May. At length all
the eggs are laid, and the bees, without any distinction as to what does or does
not belong to them, all set to work on a common shelter of the colony—a thick
bed of mortar, filling up spaces and covering all the cells. In the end the nests
look like a large mass of dry mud—very irregular, arched, thickest in the middle,
the primitive kernel of the establishment, thinnest at the edges, where there are
fewest cells, and very variable in extent, according to the number of workers,
and consequently to the time when the nest was begun. Some are not much
larger than one’s hand, while others will occupy the greater part of the edge of a
roof, and be measured by square yards. [288]
If Chalicodoma sicula works alone, as she often does, on the shutter of an

unused window or on a stone or a branch, she behaves in just the same way.
For instance, if the nest is on a bough, she begins by solidly fixing the basis of
her cell on the slender twig. Then the building rises into a little vertical tower.
This cell being stored and ceiled, another follows, supported both by the bough
and the first cell, until six to ten cells are grouped one beside the other, and
finally a general cover of mortar encloses them all together with the bough,
which gives them a firm foundation. [289]
[Contents]
XXI
EXPERIMENTS
Built on small pebbles which one can carry whither one will, remove,
or interchange, without disturbing either the work of the constructor
or the quiet of the inhabitants of the cells, the nests of Chalicodoma
muraria lend themselves readily to experiment—the only method
capable of throwing a little light on the nature of instinct. Profitably to
study the physical faculties of the animal it is not enough to know
how to turn to account such circumstances as a happy chance may
offer to the observer: one must be capable of originating others, and
vary them as much as possible and submit them to mutual control; in
short, to give science a solid basis of fact one must experiment.
Then some day will vanish before the evidence of exact documents
the fantastic legends which cumber our books, such as the
Scarabæus inviting his comrades to help in dragging his ball out of a
rut, or a Sphex cutting up a fly to carry it in spite of the wind, and
much more which is misused by those who desire to see in the
animal world that which is not there. Thus, too, will materials be
prepared which, used sooner or later by a learned [290]hand, will cast
premature and baseless theories back into oblivion.
Réaumur generally confines himself to stating facts as they offered

themselves to him in the normal course of things, and does not
attempt to penetrate further into the powers of the insect by means
of conditions brought about artificially. In his day there was
everything to do, and the harvest was so great that the illustrious
reaper hurried on to what was most urgent,—the gathering of it in,
leading his successors to examine grain and ear in detail.
Nevertheless, he mentions an experiment made on Chalicodoma
muraria by his friend Du Hamel. The nest was placed in a glass
funnel, the mouth of which was closed by a piece of gauze. Three

(Download PDF) The MD Anderson Manual of Medical Oncology 4Th Edition Hagop Kantarjian Full Chapter PDF

Uploaded by

Copyright:

Available Formats

You might also like

(Download PDF) The MD Anderson Manual of Medical Oncology 4Th Edition Hagop Kantarjian Full Chapter PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

(Download PDF) The MD Anderson Manual of Medical Oncology 4Th Edition Hagop Kantarjian Full Chapter PDF

Uploaded by

Copyright:

Available Formats

The MD Anderson Manual of Medical

Oncology 4th Edition Hagop Kantarjian

The MD Anderson Manual of Medical Oncology 3rd Edition

Sectional Anatomy by MRI and CT 4th Edition Mark W.

Diagnostic Pathology: Molecular Oncology 2nd Edition

Psycho-Oncology 4th Edition William Breitbart (Editor)

Principles of medical biochemistry 4th edition Edition

DiSaia and Creasman Clinical Gynecologic Oncology 10th

(eBook PDF) Essentials of Medical Language 4th Edition

Escourolle and Poirier's Manual of Basic Neuropathology

eBook conversion by codeMantra

Contributors xi 9. aggrssv B-Cll Lyphos 191

Vi GaSTROiNTeSTiNaL 39. Ovrn Cncr 897

29. Blry Trct Cncr 647 ix GeNiTOuRiNaRY

44. Blddr Cncr 1027 55. Cncr Gnocs 1283

45. Prostt Cncr 1049 56. ino-oncology 1297

46. Pnl Cncr 1071 57. Trgtd Thrpy n Cncr 1323

NeuROLOGiC TumORS 59. Fngl inctons n Ptnts wth

61. Oncologc ergncs 1407

62. Oncocrdology 1435

xiV SuPPORTiVe aND PaLLiaTiVe

52. Th acqrd inodfcncy 66. intgrtd Otptnt

53. Crcno o unknown Prry 1253 67. Rhbltton 1529

54. Pdtrc Cncrs 1271 68. Pn mngnt nd Sypto

70. Bg D nd Mhne Lernng

69 . sl Degn fr onlgy clnl 71. Vlue-Bed onlgy 1603

Hind Raei, MD Joseph D. Khoury, MD

Elias J. Jabbour, MD William G. Wierda, MD, PhD

Tapan M. Kadia Koji Sasaki, MD, PhD

Elias Jabbour, MD Srdan Verstovsek, MD, PhD

Prithviraj Bose, MD Raphael Steiner, MD

Lucia Masarova, MD Jason R. Westin, MD

Hesham M. Amin, MD, MSc Sergej N. Konoplev, MD, PhD

Luis E. Fayad, MD Gregory P. Kauman, MD

Preetesh Jain, MBBS, MD, DM, PhD Muzaar H. Qazilbash, MD

Sairah Ahmed Samer A. Srour, MB ChB, MS

Carl M. Gay, MD, PhD Amy Moreno, MD

Marcelo V. Negrao Robert A. Wol, MD

Ruth Sacks, MD Shalini Makawita, MD

Yun Shin Chun, MD, FACS Rony Avritscher

Van Morris, MD Bora Lim, MD

Jessica E. Maxwell, MD, MBA Rachel M. Layman, MD

Daniel M. Halperin, MD Lauren P. Cobb, MD

Mariana Chavez-MacGregor, MD Amir A. Jazaeri, MD

Haven R. Garber, MD, PhD Michaela A. Onstad, MD, MPH

Meghan S. Karuturi, MD Shannon N. Westin, MD, MPH

Karen H. Lu, MD Jose A. Karam, MD, FACS

Pedro T. Ramirez, MD Ashish M. Kamat, MD

Andrew W. Hahn, MD Paul G. Corn, MD

Jad Chahoud, MD, MPH Houssein Saa, MD

John de Groot, MD Ravin Ratan, MD

Vinod Ravi, MD Jason A. Willis, MD

Ha Nguyen, MD Zhijing Zhang

Mouhammed Amir Habra, MD Andy Futreal

Branko Cuglievan, MD James P. Allison, PhD

Wafk Zaky, MD Padmanee Sharma, MD, PhD

Richard Gorlick, MD Rabih Said, MD, MPH

Fareed Khawaja, MD Sai-Ching Jim Yeung